Topical Nsaids for Chronic Musculoskeletal Pain in Adults (Review)

Cochrane Database of Systematic Reviews

Topical NSAIDs for chronic musculoskeletal pain in adults (Review)

Derry S, Conaghan P, Da Silva JAP, Wiffen PJ, Moore RA

Derry S, Conaghan P, Da Silva JAP, Wiffen PJ, Moore RA. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD007400. DOI: 10.1002/14651858.CD007400.pub3. www.cochranelibrary.com

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. TABLE OF CONTENTS HEADER...... 1 ABSTRACT ...... 1 PLAINLANGUAGESUMMARY ...... 2 SUMMARY OF FINDINGS FOR THE MAIN COMPARISON ...... 4 BACKGROUND ...... 6 OBJECTIVES ...... 7 METHODS ...... 7 RESULTS...... 10 Figure1...... 11 Figure2...... 14 Figure3...... 16 Figure4...... 17 Figure5...... 20 DISCUSSION ...... 22 Figure6...... 23 AUTHORS’CONCLUSIONS ...... 24 ACKNOWLEDGEMENTS ...... 25 REFERENCES ...... 26 CHARACTERISTICSOFSTUDIES ...... 31 DATAANDANALYSES...... 73 Analysis 1.1. Comparison 1 Topical diclofenac versus carrier, Outcome 1 Clinical success...... 74 Analysis 1.2. Comparison 1 Topical diclofenac versus carrier, Outcome 2 Local adverse events...... 75 Analysis 1.3. Comparison 1 Topical diclofenac versus carrier, Outcome 3 Systemic adverse events...... 76 Analysis 1.4. Comparison 1 Topical diclofenac versus carrier, Outcome 4 Gastrointestinal adverse events. . . . . 77 Analysis 1.5. Comparison 1 Topical diclofenac versus carrier, Outcome 5 Withdrawals due to adverse events. . . . 78 Analysis 1.6. Comparison 1 Topical diclofenac versus carrier, Outcome 6 Withdrawals due to lack of efficacy. . . . 79 Analysis 2.1. Comparison 2 Topical ketoprofen versus carrier, Outcome 1 Clinical success...... 80 Analysis 2.2. Comparison 2 Topical ketoprofen versus carrier, Outcome 2 Local adverse events...... 81 Analysis 2.3. Comparison 2 Topical ketoprofen versus carrier, Outcome 3 Gastrointestinal adverse events. . . . . 82 Analysis 2.4. Comparison 2 Topical ketoprofen versus carrier, Outcome 4 Withdrawals due to adverse events. . . . 83 Analysis 2.5. Comparison 2 Topical ketoprofen versus carrier, Outcome 5 Withdrawals due to lack of efficacy. . . . 84 Analysis 3.1. Comparison 3 Topical NSAID versus oral NSAID, Outcome 1 Clinical success...... 85 Analysis 3.2. Comparison 3 Topical NSAID versus oral NSAID, Outcome 2 Local adverse events...... 86 Analysis 3.3. Comparison 3 Topical NSAID versus oral NSAID, Outcome 3 Gastrointestinal adverse events. . . . 87 Analysis 3.4. Comparison 3 Topical NSAID versus oral NSAID, Outcome 4 Withdrawals due to adverse events. . . 88 Analysis 3.5. Comparison 3 Topical NSAID versus oral NSAID, Outcome 5 Withdrawals due to lack of efficacy. . . 89 APPENDICES ...... 89 WHAT’SNEW...... 111 HISTORY...... 112 CONTRIBUTIONSOFAUTHORS ...... 112 DECLARATIONSOFINTEREST ...... 112 SOURCESOFSUPPORT ...... 113 DIFFERENCES BETWEEN PROTOCOL AND REVIEW ...... 113 INDEXTERMS ...... 113

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) i Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. [Intervention Review] Topical NSAIDs for chronic musculoskeletal pain in adults

Sheena Derry1, Philip Conaghan2, José António P Da Silva3, Philip J Wiffen1, R Andrew Moore1

1Pain Research and Nufﬁeld Department of Clinical Neurosciences (Nufﬁeld Division of Anaesthetics), University of Oxford, Oxford, UK. 2Leeds Institute of Rheumatic and Musculoskeletal Medicine, Faculty of Medicine and Health, University of Leeds, Leeds, UK. 3Reumatologia, Hospitais da Universidade (SRHUC), Coimbra, Portugal

Contact address: Sheena Derry, Pain Research and Nufﬁeld Department of Clinical Neurosciences (Nufﬁeld Division of Anaesthetics), University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, OX3 7LE, UK. [email protected].

Editorial group: Cochrane Pain, Palliative and Supportive Care Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 4, 2016. Review content assessed as up-to-date: 3 February 2016.

Citation: Derry S, Conaghan P, Da Silva JAP, Wiffen PJ, Moore RA. Topical NSAIDs for chronic musculoskeletal pain in adults. Cochrane Database of Systematic Reviews 2016, Issue 4. Art. No.: CD007400. DOI: 10.1002/14651858.CD007400.pub3.

ABSTRACT

Background

Use of topical nonsteroidal anti-inﬂammatory drugs (NSAIDs) to treat chronic musculoskeletal conditions has become widely accepted because they can provide pain relief without associated systemic adverse events. This review is an update of ’Topical NSAIDs for chronic musculoskeletal pain in adults’, originally published in Issue 9, 2012.

Objectives

To review the evidence from randomised, double-blind, controlled trials on the efﬁcacy and safety of topically applied NSAIDs for chronic musculoskeletal pain in adults.

Search methods

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, and our own in-house database; the date of the last search was February 2016. We also searched the references lists of included studies and reviews, and sought unpublished studies by asking personal contacts and searching online clinical trial registers and manufacturers’ web sites.

Selection criteria

We included randomised, double-blind, active or inert carrier (placebo) controlled trials in which treatments were administered to adults with chronic musculoskeletal pain of moderate or severe intensity. Studies had to meet stringent quality criteria and there had to be at least 10 participants in each treatment arm, with application of treatment at least once daily.

Data collection and analysis

Two review authors independently assessed studies for inclusion and extracted data. We used numbers of participants achieving each outcome to calculate risk ratio and numbers needed to treat (NNT) or harm (NNH) compared to carrier or other active treatment. We were particularly interested to compare different formulations (gel, cream, plaster) of individual NSAIDs. The primary outcome was ’clinical success’, deﬁned as at least a 50% reduction in pain, or an equivalent measure such as a ’very good’ or ’excellent’ global assessment of treatment, or ’none’ or ’slight’ pain on rest or movement, measured on a categorical scale.

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 1 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Main results We identified five new studies for this update, which now has information from 10,631 participants in 39 studies, a 38% increase in participants from the earlier review; 33 studies compared a topical NSAID with carrier. All studies examined topical NSAIDs for treatment of osteoarthritis, and for pooled analyses studies were generally of moderate or high methodological quality, although we considered some at risk of bias from short duration and small size. In studies lasting 6 to 12 weeks, topical diclofenac and topical ketoprofen were significantly more effective than carrier for reducing pain; about 60% of participants had much reduced pain. With topical diclofenac, the NNT for clinical success in six trials (2343 participants) was 9.8 (95% confidence interval (CI) 7.1 to 16) (moderate quality evidence). With topical ketoprofen, the NNT for clinical success in four trials (2573 participants) was 6.9 (5.4 to 9.3) (moderate quality evidence). There was too little information for analysis of other individual topical NSAIDs compared with carrier. Few trials compared a topical NSAID to an oral NSAID, but overall they showed similar efficacy (low quality evidence). These efficacy results were almost completely derived from people with knee osteoarthritis. There was an increase in local adverse events (mostly mild skin reactions) with topical diclofenac compared with carrier or oral NSAIDs, but no increase with topical ketoprofen (moderate quality evidence). Reporting of systemic adverse events (such as gastrointestinal upsets) was poor, but where reported there was no difference between topical NSAID and carrier (very low quality evidence). Serious adverse events were infrequent and not different between topical NSAID and carrier (very low quality evidence). Clinical success with carrier occurred commonly - in around half the participants in studies lasting 6 to 12 weeks. Both direct and indirect comparison of clinical success with oral placebo indicates that response rates with carrier (topical placebo) are about twice those seen with oral placebo. A substantial amount of data from completed, unpublished studies was unavailable (up to 6000 participants). To the best of our knowledge, much of this probably relates to formulations that have never been marketed. Authors’ conclusions Topical diclofenac and topical ketoprofen can provide good levels of pain relief beyond carrier in osteoarthritis for a minority of people, but there is no evidence for other chronic painful conditions. There is emerging evidence that at least some of the substantial placebo effects seen in longer duration studies derive from effects imparted by the NSAID carrier itself, and that NSAIDs add to that.

PLAIN LANGUAGE SUMMARY Topical nonsteroidal anti-inﬂammatory drugs for chronic musculoskeletal pain in adults Bottom line Topical diclofenac and topical ketoprofen can provide good levels of pain relief in osteoarthritis, but only for about 10% more people than get this result with topical placebo. There is no evidence for other chronic painful conditions. Background Chronic musculoskeletal pain occurs in conditions like osteoarthritis. Pain is typically moderate or severe in intensity, lasting for three months or more. Topical nonsteroidal anti-inﬂammatory drugs (NSAIDs) are applied to unbroken skin where it hurts in the form of a gel, cream, spray, or plaster. Topical NSAIDs penetrate the skin, enter tissues or joints, and reduce processes that cause pain in the tissue. Drug levels in the blood with topical NSAIDs are very much lower than with the same drug taken by mouth. This minimises the risk of harmful effects. Study characteristics This review is an update of ’Topical NSAIDs for chronic musculoskeletal pain in adults’, originally published in 2012. We found 39 generally high-quality studies with 10,631 participants where topical NSAID was used at least once a day. These studies tested a number of different topical drugs, mostly against a topical placebo. We were interested in participants having good pain reduction (by about half), ideally 6 to 12 weeks after treatment started. Studies that last longer are more representative of the real world, because in these chronic conditions the pain almost never goes away if untreated. We looked at individual NSAIDs to see how effective they were.

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 2 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Key results Diclofenac and ketoprofen were the only two with good quality and longer duration studies, mostly in people aged over 40 years with painful knee arthritis. The comparison was between topical diclofenac or ketoprofen in a solution or gel, and the solution or gel without any drug in it (topical placebo). For diclofenac and ketoprofen, about 6 people out of 10 with osteoarthritis had much reduced pain after 6 to 12 weeks, compared with 5 out of 10 with topical placebo (moderate quality evidence). Skin reactions (mostly mild) were more common (20 in 100) with topical diclofenac than topical placebo (5 in 100); there was no difference between topical ketoprofen and topical placebo (moderate quality evidence). Other adverse events, like stomach upsets, were poorly reported in these studies, but were no different between topical diclofenac or ketoprofen and topical placebo (very low quality evidence). Serious adverse events were uncommon. Quality of the evidence We rated the quality of the evidence for topical diclofenac and topical ketoprofen compared with placebo as moderate for efﬁcacy, and very low for harmful effects. Moderate quality evidence means that further research may change our estimate of the effect, and very low quality evidence means that we are very uncertain about the accuracy of our estimate.

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 3 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The ( 2016 adults © in Copyright pain musculoskeletal chronic for NSAIDs Topical SUMMARYOFFINDINGSFORTHEMAINCOMPARISON [Explanation]

Topical NSAIDs compared with topical placebo for chronic musculoskeletal pain in adults

Patient or population: adults with chronic musculoskeletal pain (osteoarthritis) Settings: community Intervention: topical NSAID (topical diclofenac and ketoprofen only for efficacy outcomes); treatment duration 6 to 12 weeks Comparison: topical placebo

Probable outcome with Probable outcome with Probable outcome with RR,NNT,NNTp,orNNH No of studies, partici- Quality of the evidence Comments intervention intervention comparator (95%CI) pants (GRADE)

Topical diclofenac gel 600 in 1000 500 in 1000 RR1.2 (1.1 to 1.3) 6 studies Moderate Adequate numbers of or solution NNT 9.8 (7.1 to 16) 2342 participants studies, participants,

Review) Clinical success (for and events,and consis- h ie os Ltd. Sons, & Wiley ohn example 50%reduction tency of effect, but the in pain) size of the effect was modest and could be overturned by null effect studies

Topical ketoprofen gel 630 in 1000 480 in 1000 RR1.1 (1.01 to 1.2) 4 studies Moderate Adequate numbers of Clinical success (for NNT 6.9 (5.4 to 9.3) 2573 participants studies, participants, example 50%reduction and events, but there in pain) was inconsistency of effect between studies (I2 = 83%). The size of the effect was modest and could be overturned by null effect studies

Topical diclofenac gel 140 in 1000 78 in 1000 RR1.8 (1.5 to 2.2) 15 studies Moderate Adequate numbers of or solution NNH 16 (12 to 23) 3658 participants studies, participants, Local adverse events and events, but there was inconsistency of effect (I2 = 76%), pos- 4 oyih 06TeCcrn olbrto.Pbihdb J by Published Collaboration. Cochrane The ( 2016 adults © in Copyright pain musculoskeletal chronic for NSAIDs Topical

sibly due to differences in data collection. The size of the effect was modest and could be overturned by additional studies

Topical ketoprofen gel 150 in 1000 130 in 1000 RR1.0 (0.85 to 1.3) 4 studies Moderate Adequate numbers of Local adverse events 2621 participants studies, participants, and events,and consistency of effect (no effect),but thesizeof the effect was modest and could be overturned by

Review) additional studies h ie os Ltd. Sons, & Wiley ohn Systemic adverse Poor reporting of systemic adverse events,but no difference between active and placebo,however Low quality Adequate numbers of events reported studies and participants, and consistency of effect (noeffect),but few events and poor, inconsistent reporting. Fewer than half of eligible studies reported this event

Seriousadverse events In topical NSAID versus placebo,30 serious adverse events split equally between treatments Very low quality The majority of studies did not report this outcome, few events

GRADEWorking Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.

CI: confidence interval; RR: risk ratio; NNT: number needed to treat; NNTp: number needed to prevent an event happening; NNH: number needed to harm;NSAID: nonsteroidal anti-inflammatory drug 5 BACKGROUND capsule, and mild synovitis. Trauma to the joint triggers a repair process that can result in a joint that is temporarily symptom-free, This review is an update of a review of topical nonsteroidal anti- but structurally altered. When the repair process is not adequate inflammatory drugs (NSAIDs) for chronic musculoskeletal pain the joint becomes symptomatic (NICE 2014). in adults, originally published in Issue 9, 2012 (Derry 2012a). The use of topical NSAIDs for pain relief has been a controversial subject in analgesic practice. In some parts of the world (much of Description of the intervention Western Europe, for instance) they have been available for many NSAIDs reversibly inhibit cyclooxygenase (prostaglandin en- years, are widely available without prescription, widely advertised, doperoxide synthase), the enzyme mediating production used extensively, and evidence for their use is considered adequate. of prostaglandins and thromboxane A2 (Fitzgerald 2001). In other parts of the world they were regarded as little more than Prostaglandins mediate a variety of physiological functions such placebo, with any apparent effect attributed to the process of rub- as maintenance of the gastric mucosal barrier, regulation of renal bing at the site of the affected area. In some places (the United blood flow, and regulation of endothelial tone. They also play an States (US), for instance) their use was almost unknown until 5 important role in inflammatory and nociceptive processes. to 10 years ago. In England 5.8 million prescriptions for topical NSAIDs taken orally or intravenously are transported to all parts NSAIDs were dispensed in the community in 2014 (PCA 2015), of the body in the blood, and relatively high blood concentrations mainly for formulations of ibuprofen (3 million) and diclofenac are needed to achieve effective tissue concentrations at the site of (1.5 million). the pain and inflammation. These high concentrations throughout There is good evidence for the efficacy of topical NSAIDs in acute the body can give rise to a number of adverse events that can and chronic musculoskeletal pain (Mason 2004a; Mason 2004b; be unpleasant (for example, dyspepsia) or potentially serious (for Moore 1998a). In the US the Food and Drug Administration li- example, gastrointestinal bleeding or myocardial infarction). censed topical nonsteroidal products in 2007, and in England the A topical medication is one applied to body surfaces such as the National Institute for Clinical Excellence (NICE) recommended skin or mucous membranes to treat ailments. A large range of types topical therapies as first line treatment in its guidelines for os- of topical formulation may be used, including but not limited to teoarthritis in 2008 and updated guidance in 2014 (NICE 2008; creams, foams, gels, lotions, ointments, and plasters. The exact NICE 2014). Earlier reviews of topical analgesics cover not only formulation of a topical medication is often determined by how clinical trials, but also studies investigating the underlying science fast drug absorption is wanted. Plasters containing drug reservoirs to explain biological plausibility (Bandolier 2005; Moore 2008a). result in slow absorption rates, lower blood levels, and reduced first pass effect in the liver. They have been used especially for This review is one of a series on topical analgesics, including top- transdermal opioids or contraceptive steroids. Other formulations ical capsaicin at low and high doses (Derry 2012b; Derry 2013), and topical NSAIDs in acute pain conditions (Derry 2015), and add substances that improve skin penetration, in trying to achieve salicylate-containing rubefacients (Derry 2014). higher levels in the tissue rather than the blood. This effect has been sought with gels and plasters of NSAIDs. Topical NSAIDs are formulated for direct application to the painful site, and to produce a local pain-relieving effect while Description of the condition avoiding body-wide distribution of the drug at physiologically ac- We searched for studies treating any chronic pain condition with tive levels (McPherson 2013). This method of application (dos- a topical NSAID, but the only studies identified were in chronic ing) necessarily limits their use to more superficial painful con- pain caused by osteoarthritis. ditions such as osteoarthritis of the knee or hand. They would Osteoarthritis is the most common form of joint disease and a not, for example, be indicated for deep visceral pain, deep-seated leading cause of pain, physical disability, and reduced quality of joints such as the hip or the spine, or headaches. They are also not life throughout the world. It is a major part of musculoskeletal appropriate for use on broken skin, so would not be used on open disorders, and a major cause of disability in the community (Vos wounds (accidental or surgical). 2012). Osteoarthritis particularly affects older people. Symptoms Topical placebo has frequently been used in studies in order to include pain, tenderness, and stiffness in the affected joint, all demonstrate the benefits of topical NSAID. Topical placebo has which can affect function. If the pain level prevents movement, been thought to be inert, and without any analgesic effect of its the associated muscles may atrophy (waste) and ligaments become own. However, in recent studies that compared a ketoprofen gel lax. The most commonly affected joints are the knees, hands, and formulation (IDEA-033) with the gel carrier (TDT-064) the anal- hips (NICE 2014). gesic effect was almost equivalent to that of the ketoprofen gel, Osteoarthritis is characterised by localised areas of loss of articular and with a significantly larger effect than oral placebo. It is sug- cartilage in the joint, accompanied by subchondral bone changes, gested that this is due to a ’biolubrication’ mechanism (Conaghan osteophyte formation at the joint margins, thickening of the joint 2014). Whether this is true, and whether there is any special ben-

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 6 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. eﬁt of one carrier over another, is speculative. For the purposes of pain (Derry 2015), topical salicylate-containing rubefacients for this update, we have chosen to use the term ’carrier’ rather than acute and chronic musculoskeletal pain (Derry 2014), and topical ’placebo’ except for oral placebos. capsaicin for neuropathic pain (Derry 2012b; Derry 2013).

How the intervention might work For a topical formulation to be effective, it must first penetrate the OBJECTIVES skin. Only when the drug has entered the lower layers of the skin can it be absorbed by blood, or penetrate deeper into areas where Toreview the evidence from randomised, double-blind, controlled inflammation occurs. Individual drugs have different degrees of trials on the efficacy and safety of topically applied NSAIDs for penetration. A balance between lipid and aqueous solubility is chronic musculoskeletal pain in adults. needed to optimise penetration, and use of prodrug esters has been suggested as a way of enhancing permeability. Formulation is also crucial to good skin penetration, and efficacy has to be METHODS judged on formulation - including drug concentration - as well as drug. Experiments with artificial membranes or human epidermis suggest that creams are generally less effective than gels or sprays, but newer formulations such as microemulsions may have greater Criteria for considering studies for this review potential (Moore 2008a). Once the drug has reached the site of action, it must be present at a sufficiently high concentration to inhibit cyclooxygenase enzymes Types of studies and produce pain relief. It is probable that topical NSAIDs exert We included randomised, controlled, double-blind trials compar- their action both by local reduction of symptoms arising from peri- ing topical NSAIDs with inert carrier (placebo) or other active articular structures, and by systemic delivery to intracapsular struc- treatment for chronic musculoskeletal pain, with at least 10 par- tures. Tissue levels of NSAIDs applied topically certainly reach ticipants per treatment arm and duration of at least two weeks, al- levels high enough to inhibit cyclooxygenase-2 (Bandolier 2005; though we were particularly interested in outcomes at six weeks or Haroutiunian 2010; Moore 2008a). Plasma concentrations found longer. We excluded studies published only as short (conference) after topical administration, however, are only a fraction (usually abstracts or studying experimentally induced pain. We considered much less than 5%) of the levels found in plasma following oral studies using a cross-over design only if data from the first treat- administration. Topical application can potentially limit systemic ment period were reported separately. adverse events by increasing local effects, and minimising systemic concentrations of the drug. We know that upper gastrointestinal bleeding is low with chronic use of topical NSAIDs (Evans 1995), Types of participants but have no certain knowledge of lower effects on heart failure, or Adult participants (16 years or more) with chronic musculoskele- renal failure, both of which are associated with oral NSAID use. tal pain of at least three months’ duration and at least moderate intensity. We excluded studies examining participants with neuropathic pain or fibromyalgia. Why it is important to do this review Since the last review in 2012, a number of new studies have Types of interventions been published, mainly involving topical ketoprofen formulations. These new studies are generally of higher quality than many of the Included studies had at least one treatment arm using a topical earlier ones in this review, and have the potential to substantially NSAID, and a comparator arm using inert carrier alone or an active influence the strength of its conclusions. Moreover, the additional analgesic intervention such as an oral NSAID. Topical NSAIDs information allows for analysis based not only on a particular drug, had to be applied at least once daily. We did not include salicylates but also on the formulation of that drug. This can provide bet- because they are no longer classified as topical NSAIDs and are ter insight into whether formulation affects the efficacy of topical covered in a separate review (Derry 2014). NSAIDs in chronic musculoskeletal pain. An updated review of evidence for topical NSAIDs is needed to inform choices made by consumers, prescribers, and commission- Types of outcome measures ers (purchasers of health care). This is one of a series of reviews We sought information on participant characteristics: age, sex, and being conducted on topical analgesics, including NSAIDs in acute condition to be treated.

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 7 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Primary outcomes See Appendix 1 for the CENTRAL search strategy, Appendix 2 for The primary outcome was ’clinical success’, defined as at least a the MEDLINE search strategy, and Appendix 3 for the EMBASE 50% reduction in pain, or an equivalent measure such as a ’very search strategy. good’ or ’excellent’ global assessment of treatment, or ’none’ or ’slight’ pain on rest or movement, measured on a categorical scale Searching other resources (Moore 1998a; Moore 2013). We used the following hierarchy of We searched the reference lists of review articles and included outcomes, in order of preference, to extract data for the primary studies. Manufacturers have previously been asked for details of outcome: unpublished studies (Derry 2012a; Mason 2004b), and we did • Participant-reported reduction in pain of at least 50%. not approach them again for this review. • Participant-reported global assessment of treatment. We searched clinical trial registries (clinicaltrials.gov and the World • Pain on movement. Health Organization International Clinical Trials Registry Plat- • Pain at rest or spontaneous pain. form) and asked personal contacts for information about ongoing If none of these measures were available we used undefined ’im- and unpublished studies. provement’ where it was reported. We used only participant-reported outcomes of efficacy, and not physician or investigator-reported outcomes. Data collection and analysis We did not blind review authors to the authors’ names and insti- Secondary outcomes tutions, journal of publication, or study results at any stage of the • Numbers of participants with adverse events: local and review. We resolved disagreements through discussion. systemic, and particularly serious gastrointestinal problems. • Numbers of withdrawals: all cause, lack of efficacy, and Selection of studies adverse events. Two review authors independently screened the titles and abstracts We anticipated that outcomes would be reported after different of each study identified by the search to eliminate those that clearly durations of treatment, and extracted results for any treatment did not satisfy the inclusion criteria, and obtained full copies of duration of two weeks or more, with longer durations of treatment the remaining studies. The same authors then independently read preferred because of potential bias in short duration studies (PaPaS these studies to determine eligibility. 2012). We also anticipated that reporting of adverse events would vary between studies with regard to the terminology used, method of ascertainment, and categories reported (occurring in at least 5% Data extraction and management of participants or where there is a statistically significant difference Two review authors independently extracted information about between treatment groups). We took care to identify these details the participants, the intervention, and the study design using a where relevant. standard data extraction form. One review author entered data suitable for meta-analysis into RevMan 5.3 (RevMan 2014), and another checked it. Search methods for identification of studies Assessment of risk of bias in included studies Electronic searches We used the Oxford Quality Score as the basis for inclusion, limiting inclusion to studies that were randomised and double-blind We searched the following databases: as a minimum (Jadad 1996b). • Cochrane Central Register of Controlled Trials Two authors independently assessed risk of bias for each study us- (CENTRAL 2012, Issue 5) for the original review, and via the ing the criteria outlined in the Cochrane Handbook for Systematic Cochrane Register of Studies Online (CRSO) to 3 February Reviews of Interventions with any disagreements resolved by dis- 2016 for this update. cussion (Chapter 8.5, Higgins 2011). We assessed the following • MEDLINE (via Ovid) (from 2004 to 7 June 2012 for the for each study. original review, and to 3 February 2016 for this update). 1. Random sequence generation (checking for possible • EMBASE (via Ovid) (2004 to 7 June 2012 for the original selection bias). We assessed the method used to generate the review, and to 3 February 2016 for this update). allocation sequence as: low risk of bias (any truly random • Oxford Pain Relief Database, Jadad 1996a, for the original process, for example, random number table; computer random review. This resource is no longer being updated. number generator); unclear risk of bias (method used to generate There was no language restriction. sequence was not clearly stated). We excluded studies using a

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 8 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. non-random process, which were therefore at high risk of bias the term the number needed to treat for an additional harmful (for example, odd or even date of birth; hospital or clinic record outcome (NNH). number). We did not use continuous data because it is inappropriate where 2. Allocation concealment (checking for possible selection there is an underlying skewed distribution, as is usually the case bias). The method used to conceal allocation to interventions with analgesic response (Moore 2010a). before assignment determines whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment. We assessed the methods as: low Unit of analysis issues risk of bias (for example, telephone or central randomisation; Randomisation was to the individual participant. consecutively numbered, sealed, opaque envelopes); unclear risk of bias (method was not clearly stated). We excluded studies that did not conceal allocation and were therefore at high risk of bias Dealing with missing data (for example, open list). Wherever possible we used intention-to-treat (ITT) analysis where 3. Blinding of outcome assessment (checking for possible the ITT population consists of participants who were randomised, detection bias). We assessed the methods used to blind study applied at least one dose of the assigned study medication, and participants and outcome assessors from knowledge of which provided at least one post-baseline assessment. We assigned miss- intervention a participant received. We assessed the methods as: ing participants zero improvement. low risk of bias (study stated that it was blinded and described We also looked for information about methods of imputation for the method used to achieve blinding, for example, identical missing data. tubes containing gel, or identical plasters; matched in appearance and smell); unclear risk of bias (study stated that it was blinded but did not provide an adequate description of how blinding was Assessment of heterogeneity achieved). We excluded studies that were not double-blind and We examined heterogeneity visually using L’Abbé plots (L’Abbé therefore at high risk of bias. 1987), a visual method for assessing differences in results of indi- 4. Incomplete outcome data (checking for possible attrition vidual studies, and with the I2 statistic. bias due to the amount, nature, and handling of incomplete outcome data). We assessed the methods used to deal with Assessment of reporting biases incomplete data as: low risk of bias (less than 10% of participants did not complete the study or used ’baseline The aim of this review was to use dichotomous data of known observation carried forward’ analysis, or both); unclear risk of utility (Moore 2013). The review did not depend on what the bias (used ’last observation carried forward’ (LOCF) analysis); or authors of the original studies chose to report or not. Studies that high risk of bias (used ’completer’ analysis). did not report dichotomous results, but only average pain data, 5. Size (checking for possible biases confounded by small size). did not contribute to analyses (Moore 2010a). Small studies have been shown to overestimate treatment effects, We assessed publication bias using a method designed to detect the probably due to methodological weaknesses (Dechartres 2013; amount of unpublished data with a null effect required to make Nüesch 2010). We assessed studies as at low risk of bias if they any result clinically irrelevant (usually taken to mean a NNT of had at least 200 participants per treatment arm, at unclear risk if 10 or higher; Moore 2008b). they had 50 to 200 participants per treatment arm, and at high risk if they had fewer than 50 participants per treatment arm. Data synthesis We analysed data by the individual NSAID and comparator; for Measures of treatment effect example, we analysed topical diclofenac versus carrier (topical We used risk ratio (RR) to establish statistical difference and num- placebo), and topical diclofenac versus active comparator, whether bers needed to treat for an additional beneficial outcome (NNT) that was an oral NSAID, a different topical NSAID, or a different and pooled percentages as absolute measures of benefit or harm. (non-NSAID) topical treatment. For topical NSAID versus car- We used the following terms to describe adverse outcomes in terms rier, we split the analyses according to the duration of the study of harm or prevention of harm. (2 to ≤ 6 weeks, and 6 to 12 weeks), and the particular topical • When significantly fewer adverse outcomes occurred with formulation used (plaster versus gel, cream, spray, or solution). treatment than with control (placebo or active), we used the term Where appropriate, we pooled data for each dichotomous out- the number needed to treat to prevent one additional outcome come and calculated RR with 95% confidence intervals (CI) using (NNTp). the fixed-effect model (Morris 1995). We assumed a statistically • When significantly more adverse outcomes occurred with significant benefit of active treatment over control when the lower treatment compared with control (placebo or active), we used limit of the 95% CI of the relative benefit is greater than one, and

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 9 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. for control over active treatment when the upper limit of the 95% Description of studies CI is less than one. We calculated NNTs and NNHs with 95% CIs by the method of Cook and Sackett (Cook 1995). We did not carry out pooled analysis where there were fewer than Results of the search 200 participants in the comparison (Moore 1998b). For this update we identified 257 studies in CENTRAL, 121 stud- We planned to test for statistically significant differences between ies in MEDLINE, and 397 studies in EMBASE. After deduplica- NNTs for different topical NSAIDs versus carrier using the z test tion and screening we obtained full copies of five published studies where there were sufficient data to do so, and where the clinical to assess them for inclusion. We excluded one study after read- trials were sufficiently similar in types of patient, outcome, and ing the full reports (Verkleij 2015), and included four (Conaghan duration to make such comparisons sensible (Tramer 1997). 2013; Kneer 2013; Rother 2013; Varadi 2013). We have re- quested full copies of two further published studies (Bohlooli 2012; Niempoog 2012), which are awaiting classification. Quality of the evidence New searches of clinical trial registries identified 17 additional Two review authors independently rated the quality of each out- reports of studies. One study satisfied inclusion criteria, was not come. We used the GRADE system to assess the quality of the published but had results posted, and is included in this re- evidence related to the key outcomes listed in Types of outcome view (NCT01980940). The remaining studies were completed, measures, as appropriate (Appendix 4; Chapter 12.2, Higgins or have passed their estimated completion date, but have no 2011). study results posted. Some studies identified in the earlier review have now been published (NCT00670475; Bohlooli 2012 and Summary of findings table NCT01496326; Varadi 2013), and two are now removed because they clearly did not satisfy our inclusion criteria; one was open- We have included a ’Summary of findings’ table, as set out in the label (NCT00372333) and the other treated neuropathic pain author guide (PaPaS 2012), and recommended in the Cochrane (NCT01508676). One study has been reported as part of a pooled Handbook (Chapter 4.6.6, Higgins 2011) to present the main analysis, and is already included in this review (NCT00426621, findings in a transparent and simple tabular format. In particular, in Baraf 2011). Some others have been presented as posters and we included key information concerning the quality of evidence, abstracts at conferences, but we have been unable to obtain suffi- the magnitude of effect of the interventions examined, and the cient details from the manufacturers to allow us to include them sum of available data on the outcomes of ’clinical success’ (for ex- in this review. ample at least 50% pain intensity reduction), local adverse events, We have assigned the status of ’ongoing study’ to three systemic adverse events, and serious adverse events. studies that were scheduled to complete in October 2014 ( NCT02121002), January 2015 (NCT02068859), and Novem- Subgroup analysis and investigation of heterogeneity ber 2015 (NCT01377038). It is possible that these studies will reach full publication. We judged that the remaining 12 completed We carried out subgroup analyses for different NSAIDs, duration studies that remain unpublished and without results in the registry of study, and topical formulation for the primary analysis (see Data report are unlikely to ever reach full publication, except possibly synthesis above). as part of a post-hoc pooled analysis, and have put them into an appendix (Appendix 5). These unpublished studies included al- Sensitivity analysis most 6000 participants. For the earlier review we identified 47 potential studies (45 pub- We did not plan any sensitivity analyses because the amount of lications) from our searches and from the earlier published re- data for individual NSAIDs was expected to be small. views (Mason 2004b; Moore 1998a); we excluded 13 studies (13 It was anticipated that data for active comparators would be very publications) from that review, leaving 34 studies (32 publica- limited, and preclude any subgroup and sensitivity analyses. tions) that satisfied our inclusion criteria. Two of the included studies were available only as a synopsis from the manufacturer (102-93-1; 108-97), and the remainder were journal publications. Together this updated review has 39 included studies (37 publi- RESULTS cations) (Figure 1).

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 11 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Tugwell 2004), celecoxib (Conaghan 2013; Roth 2004), and Included studies ibuprofen (Dickson 1991; Zacher 2001), all in tablet form. Thirty-three studies (30 publications, one registry report) com- Studies recruited male and female adults, most with a diagnosis of primary osteoarthritis of the knee or hand, with independent radi- pared a topical NSAID with carrier alone. Of these, five stud- ological confirmation of osteoarthritis within three to six months ies also included a treatment arm with oral NSAID (Conaghan before trial commencement. Some studies included other types of 2013; Rother 2007; Sandelin 1997; Simon 2009; Tugwell 2004), chronic pain and used less precise descriptions of diagnosis, such and one included a treatment arm with another non-NSAID topical treatment (McCleane 2000). Two studies compared a topi- as “soft tissue rheumatism” (Burgos 2001), “cervical and lumbar cal NSAID with a different oral NSAID (Dickson 1991; Zacher back pain” (Hohmeister 1983), and “musculoskeletal pain of at least 3 months duration” (McCleane 2000). The mean age in in- 2001), and four compared one topical NSAID with another topi- dividual studies, where reported, ranged from 59 to 65 years, and cal treatment (Balthazar-Letawe 1987; Burgos 2001; van Haselen all studies included both men and women. Participants were gen- 2000; Widrig 2007). erally excluded for pregnancy or lactation, sensitivity to NSAIDs, Three studies that are new in this update (Conaghan 2013; Kneer 2013; Rother 2013), and one from the earlier review (Rother concomitant skin disease or damage at the application site, sec- 2007), compared a ketoprofen gel formulation (IDEA-033) with ondary osteoarthritis, or systemic inflammatory disease. Participants were treated for at least two weeks (an inclusion cri- the gel carrier (TDT-064). The carrier was probably thought to terion) and for different durations up to 12 weeks. Most studies be inert in terms of analgesic activity when the trials were planned lasted two to three weeks, but the majority of participants were and carried out, but it demonstrated an analgesic effect almost in the longer duration (6 to 12 week) studies, which were more equivalent to that of the ketoprofen gel. It is suggested that this is due to a ’biolubrication’ mechanism (Conaghan 2014). recent, larger, and tended to be of higher reporting quality. Par- ticipants were usually assessed in clinic at intervals during treat- In this update 5019 participants were treated with a topical ment and sometimes also over the phone. Compliance to study NSAID, 3779 with placebo or carrier, 1591 with an oral NSAID, medication, where reported, was measured by weighing bottles at and 242 with another topical remedy (10,631 in total). In the the start of each clinic visit. Rescue medication in the form of oral previous review, the total number of participants was 7688. The paracetamol was allowed by most trials, except during 24 hours, or update has almost 3000 more participants from large studies, a 38% increase on the previous review. in some cases 48 hours, preceding the assessments. Some studies specified limits on the total amount of paracetamol allowed with- Topical NSAIDs used were diclofenac, eltenac, etoricoxib, fel- out being classified as a treatment failure; for example, 2 grams binac, flufenamate, flurbiprofen, indomethacin, ibuprofen, ke- daily on three consecutive days. Aspirin at low dose was permitted toprofen, nimesulide, piketoprofen, and piroxicam. They were for cardiovascular prophylaxis. applied as solutions, gels, or plasters (patches). Topical placebo Nearly all studies reported group mean changes (pain, physical was the carrier without the active NSAID. Seven studies used a dimethyl sulphoxide (DMSO)-based carrier (102-93-1; 108-97; function) as their primary outcomes but dichotomous outcomes suitable for a “responder analysis” were available in most or sup- Baer 2005; Bookman 2004; Rother 2007; Roth 2004; Simon plied by the manufacturer (Nuvo Research Inc for Pennsaid®). 2009), of which four undertook separate analyses of placebo with The measurement tools for documenting pain and physical func- or without DMSO (102-93-1; 108-97; Bookman 2004; Simon tion were varied and included the Osteoarthritis Research Soci- 2009). Where available we have used data for placebo with DMSO ety International Index (OARSI), Western Ontario and McMas- as the comparator. Instructions for application of topical treatments were generally clear; a set quantity of gel or solution was ap- ter Universities Arthritis Index (WOMAC: visual analogue scale or Likert), Australian/Canadian Hand Osteoarthritis Index (AUS- plied onto the affected area with gentle massage, topical solution CAN), Lequesne index, and patient global evaluation of treatment was applied around the circumference of the affected area without (PGE). massage, and patches were applied topically. Doses of drugs are not Methods used to report adverse events included patient reports, normally calculated, and treatment is defined in terms of number diary assessments, questionnaires, clinical observation, and blood of treatments each day using a specified quantity of agent (such as 40 drops of diclofenac in DMSO solution). Although the quan- testing. Adverse events were frequently separated into application- site (local) and systemic events. tity of topical agent to be applied was generally well described, Full details of included studies are in the ’Characteristics of particularly in more recent studies, the actual dose applied was not included studies’ table. always reported or easily calculated to allow comparison between studies. Oral NSAIDs used were diclofenac (Sandelin 1997; Simon 2009;

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 12 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Excluded studies cal quality using the Oxford Quality Scale. Four studies did not We excluded 15 studies after obtaining the full papers. Details are report fully on withdrawals (102-93-1; Bolten 1991; Link 1996; in the ’Characteristics of excluded studies’ table. Most exclusions Rose 1991; Varadi 2013). A breakdown of the scores can be seen were due to short duration and lack of blinding. in the ’Characteristics of included studies’ table. We also completed a ’Risk of bias’ assessment. The main deﬁcien- cies were in study duration and trial size, particularly in the older Risk of bias in included studies studies (Figure 2). Short study duration to test an intervention All studies included were both randomised and double-blind. for a chronic condition, and small study size, both tend to over- Eighteen studies were given a quality score of 5/5, 15 a score of estimate treatment effect. Newer studies tended to be of longer 4/5, ﬁve a score of 3/5, and one a score of 2/5 for methodologi- duration (up to 12 weeks) and larger.

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 13 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 2. ’Risk of bias’ summary: review authors’ judgements about each risk of bias item for each included study.

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 14 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Allocation Effects of interventions All studies were randomised, but 17 did not adequately describe See: Summary of findings for the main comparison the methods used to generate the random number sequence, and Results from individual studies are provided in Appendix 6 (effi- 25 did not adequately describe the methods used to conceal the cacy) and Appendix 7 (adverse events and withdrawals). A sum- allocation of the sequence. mary of the main results, together with a judgement on the quality of the evidence for each outcome, is presented in Summary of Blinding findings for the main comparison. All studies were blinded to both personnel and participants. Eight did not adequately describe the methods used to blind the interventions, and we judged them to be at unknown risk for this 1. Topical NSAID versus carrier (topical ’placebo’) item (102-93-1; 108-97; Balthazar-Letawe 1987; Grace 1999; Hohmeister 1983; Link 1996; Rose 1991; Rother 2013). We judged the remaining studies to be at low risk of bias for this item. Participants with ’clinical success’ There were sufficient data for pooled analysis for diclofenac and Incomplete outcome data ketoprofen only, and the calculations below are based on the def- We judged one study to be at high risk of bias for this item because inition of clinical success as at least a 50% reduction in pain, or withdrawal rates exceeded 10% and missing data were analysed an equivalent measure such as a ’very good’ or ’excellent’ global using LOCF (Burgos 2001). We judged 27 studies at unknown assessment of treatment, or ’none’ or ’slight’ pain on rest or move- risk, in most cases because they did not report the method used ment, measured on a categorical scale. to deal with missing data or withdrawals, although five of these studies did not contribute data to the primary outcome analyses (102-93-1; 108-97; Balthazar-Letawe 1987; Ottillinger 2001; Diclofenac Sandelin 1997). We judged the remaining nine studies to be at Six studies (four publications; 2343 participants) of 6 to 12 weeks’ low risk. duration provided data for this outcome; four used a gel formulation (Altman 2009; Baraf 2011), and two a solution (Baer 2005; Roth 2004). All defined ’success’ as either at least a 50% reduc- Other potential sources of bias tion in pain intensity or an Osteoarthritis Research Society Inter- Only four of the included studies had sufficient numbers of par- national Index (OARSI) response that includes response to pain, ticipants in each treatment arm (≥ 200) to be judged at low risk pain, function, and patient’s global assessment (Dougados 2000). of bias due to size (Baraf 2011; Conaghan 2013; Rother 2013; The condition studied was knee arthritis in all except one, which Tugwell 2004). Twelve studies had fewer than 50 participants per examined hand arthritis (Altman 2009). treatment arm and we judged them at high risk (102-93-1; 108-97; • The proportion of participants experiencing clinical success Balthazar-Letawe 1987; Ergun 2007; Galeazzi 1993; Grace 1999; with diclofenac was 60% (716/1185, range 44% to 66%). Gui 1982; Hohmeister 1983; McCleane 2000; NCT01980940; • The proportion of participants experiencing clinical success Rose 1991; Varadi 2013). The remaining 21 studies had between with carrier was 50% (582/1158, range 25% to 57%) (Analysis 50 and 200 participants per treatment arm. 1.1; Figure 3).

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 15 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 3. Forest plot of comparison: 8 Diclofenac versus carrier, outcome: 8.1 Clinical success.

• The risk ratio (RR) of treatment compared with carrier was tency of effect, but the size of the effect was modest and could be 1.2 (95% confidence interval (CI) 1.1 to 1.3), and the NNT was overturned by null effect studies. The short duration of the studies 9.8 (7.1 to 16). may also lead to an overestimation of effect. • For the plaster alone (258 participants) the RR was 2.7 (1.8 Restricting the analysis to knee arthritis only (1958 participants) to 3.9) and the NNT was 3.1 (2.3 to 4.6). made no difference to the results. • For the gel and solution (474 participants), the RR was 1.5 We judged the quality of this evidence as moderate; there were (1.2 to 2.0) and the NNT was 7.5 (4.6 to 20). adequate numbers of studies, participants, and events, and consistency of effect, but the size of the effect was modest and could be overturned by null effect studies. Five studies (732 participants) of 2 to < 6 weeks’ duration provided Ketoprofen data for this outcome; two used a plaster formulation (Bruhlmann Four studies (2573 participants) of 6 to 12 weeks’ duration pro- 2003; Dreiser 1993), two used a gel (Grace 1999; Niethard 2005), vided data for this outcome; all used a gel formulation (IDEA- and one used a solution (Bookman 2004). Bookman 2004 de- 033) and defined ’success’ as either at least a 50% reduction in pain fined ’success’ as at least a 50% reduction in pain intensity, and intensity or an OARSI response (Conaghan 2013; Kneer 2013; the remainder typically used patient global evaluation (PGE) cate- Rother 2013). Conaghan 2013 tested two different doses (100 mg gories of ’very good’ or ’excellent’. The condition studied was knee and 200 mg daily) and Kneer 2013 tested three doses (50 mg, arthritis in all studies. 100 mg, and 200 mg daily). There was no discernable difference • The proportion of participants experiencing clinical success between doses, so we have combined all doses for analysis. The with diclofenac was 43% (159/368, range 31% to 71%). condition studied was knee arthritis in all studies. • The proportion of participants experiencing clinical success • The proportion of participants experiencing clinical success with carrier was 23% (84/364, range 7.7% to 33%). with ketoprofen was 63% (944/1503, range 41% to 89%). • The RR of treatment compared with carrier was 1.9 (1.5 to • The proportion of participants experiencing clinical success 2.3), and the NNT was 5.0 (3.7 to 7.4) (Analysis 1.1; Figure 3). with carrier was 48% (516/1070, range 28% to 78%). We judged the quality of this evidence as moderate; there were • The RR of treatment compared with carrier was 1.1 (1.01 to adequate numbers of studies, participants, and events, and consis- 1.2), and the NNT was 6.9 (5.4 to 9.3) (Analysis 2.1; Figure 4).

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 16 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Figure 4. Forest plot of comparison: 9 Ketoprofen versus carrier, outcome: 9.1 Clinical success.

• For the 200 mg dose only (1685 participants), the RR was Rose 1991: 8/15 participants reported PGE of very good or excel- 1.1 (0.98 to 1.2); the NNT was not calculated. lent with both piroxicam gel 0.5% and carrier for two weeks.

We judged the quality of this evidence as moderate; there were Participants with local adverse events adequate numbers of studies, participants, and events, but there was inconsistency of effect (I2 = 83%) with one study showing Local adverse events were irritation of the area to which the topical a significantly worse result with ketoprofen than placebo (Rother NSAID was applied, including dry skin, redness or erythema, and 2013). Moreover, the size of the effect was modest and could be itch or pruritis. Twenty-nine studies (27 publications), with 7594 overturned by null effect studies. participants, reported information on participants in each treat- There were no studies of ketoprofen of less than six weeks’ dura- ment arm with local adverse events. Events were usually described tion. as mild and transient. There were wide variations in the incidence of events for both control (0% to 43%) and topical NSAID (0% to 51%), with a high incidence in the control arm of a study generally accompanied by Other topical NSAIDs a high incidence in the active arm. This may in part reflect differ- Single studies reported dichotomous data for ’clinical success’ for ences in the way adverse event data were collected (spontaneous etoricoxib, felbinac, nimesulide, and ibuprofen, and two reported reports, questioning, diary, checklist), and which symptoms were data for piroxicam. All were of shorter duration. There were in- recorded as adverse events. For example, one study reported that sufficient data to draw any conclusions about efficacy. 21 participants receiving active treatment and six receiving con- Bolten 1991: 34/142 participants experienced undefined ’im- trol ’developed dry skin at the application site’, but only four and provement’ in pain at rest with felbinac gel 3% for two weeks, one, respectively, were reported to have ’application site reactions’ compared with 15/139 with carrier. (102-93-1). Others reported dry skin as the most common local Ergun 2007: 23/49 participants reported PGE of very good or adverse event (Baer 2005; Bookman 2004). excellent with nimesulide gel 1% for 30 days, compared with 2/ Where data were available we have included dry skin as a local 21 with carrier. adverse event. Some studies reported the number of participants Gui 1982: 14/18 participants experience undefined ’improve- with specific local adverse events, and in these cases we have used ment’ on movement with ibuprofen cream for three weeks, com- the number for the most common event (usually dry skin); this pared with 7/19 with carrier. assumes that all those who reported dry skin also had rash or ery- McCleane 2000: 1/50 participants experienced at least a 50% thema or redness, and may slightly underestimate the total num- reduction in pain intensity with piroxicam gel 2.5% for four weeks, ber of participants with any local adverse event. Further variation compared with 4/50 with carrier. in incidence may arise due to differing treatment periods, and for NCT01980940: 13/24 participants reported a response to treat- active treatment arms variation is to be expected due to use of ment of well or very well with etoricoxib 50 mg gel for two weeks, different drugs and different strengths of the applied drug, or dif- compared with 14/24 with carrier. ferent total amounts applied.

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 17 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Diclofenac - all formulations There were too few studies, participants, and events to draw any Fifteen studies (13 publications, 3658 participants) reported on conclusions about local adverse events for any of these NSAIDs. the number of participants experiencing local adverse events with diclofenac (102-93-1; Altman 2009; Baer 2005; Baraf 2011; Bookman 2004; Bruhlmann 2003; Dreiser 1993; Galeazzi 1993; Participants with systemic adverse events Grace 1999; Niethard 2005; Roth 1995; Roth 2004; Simon 2009). There was no consistent difference in reported event rates for dif- Fourteen studies, with 2237 participants in comparisons with car- ferent formulations, so we have combined them for analysis. rier, reported information on participants with systemic adverse • The proportion of participants experiencing local adverse events in each treatment arm. Events were wide ranging, includ- events with diclofenac was 261/1842 (14%, range 0% to 51%). ing headache, diarrhoea, drowsiness, and dyspepsia, and were usu- • The proportion of participants experiencing local adverse ally described as mild. In most studies the incidence was below or events with carrier was 141/1816 (7.8%, range 0% to 43%). around 10%, and as with local adverse events, a higher incidence • The RR of treatment compared with carrier was 1.8 (1.5 to in the control arm was generally accompanied by a higher inci- 2.2), and the NNH was 16 (12 to 23) (Analysis 1.2). dence in the active arm. We judged the quality of this evidence as moderate; there were There was no difference between topical NSAID and carrier alone adequate numbers of studies, participants, and events, but there in any individual study, or for topical diclofenac (1266 partici- was inconsistency of effect (I2 = 76%), possibly due to differences pants, RR 0.89 (0.59 to 1.3)) (Analysis 1.3) or for all other topical in data collection, and the size of the effect was modest. NSAIDs combined (971 participants, RR 1.2 (0.77 to 1.8)). Many studies did not report data for participants with any systemic adverse event, but did report information either about spe- Ketoprofen cific adverse events (nausea) or events occurring within an organ Four studies (2621 participants) reported on the number of par- system (gastrointestinal). There were no significant differences in ticipants experiencing local adverse events with ketoprofen gel the incidence of gastrointestinal adverse events between any top- (Conaghan 2013; Kneer 2013; Rother 2007; Rother 2013). All ical NSAID and carrier in any individual study, or for topical di- used the same formulation (IDEA-033) and doses were 50 mg, clofenac (3240 participants, RR 1.1 (0.76 to 1.6)) (Analysis 1.4) 100 mg, and 200 mg daily. or topical ketoprofen (2621 participants, RR 0.96 (0.69 to 1.3)) • The proportion of participants experiencing local adverse (Analysis 2.3). events with ketoprofen (all doses) was 236/1542 (15%, range We judged the quality of this evidence for systemic adverse events 5.6% to 28%). as very low; there were adequate numbers of studies and partici- • The proportion of participants experiencing local adverse pants, and consistency of effect (no effect), but fewer than half of events with carrier was 139/1079 (13%, range 5.9% to 20%). eligible studies reported this outcome, reporting was inconsistent, • The RR of treatment compared with carrier was 1.0 (0.85 and there were small numbers of events. to 1.3); the NNH was not calculated (Analysis 2.2). • No individual study showed a significant difference between ketoprofen and carrier. For the 200 mg dose alone, the RR was 1.1 (0.92 to 1.4); the NNH was not calculated. Participants with serious adverse events We judged the quality of this evidence as moderate; there were Ten studies (seven publications, one registry report, 4889 partici- adequate numbers of studies, participants, and events, and con- pants) reported the occurrence of serious adverse events. sistency of effect (no effect), but the size of the effect was modest. Baraf 2011 (three studies, 1426 participants) reported 12 serious adverse events with diclofenac and five with carrier, one of which was considered to be related to the study drug. An 80-year-old Other NSAIDs woman treated with diclofenac sodium gel, who had multiple Ten studies reported on the number of participants experienc- risk factors for peripheral vascular disease, experienced deep vein ing local adverse events with eltenac (Ottillinger 2001; Sandelin thrombosis and pulmonary embolism, which was managed with 1997), felbinac (Bolten 1991), flufenamate (Hohmeister 1983), warfarin and heparin. One other participant (76-year-old male) flurbiprofen (Poul 1993), ibuprofen (Gui 1982; Varadi 2013), treated with diclofenac also had pre-existing medical problems and nimesulide (Ergun 2007), and piroxicam (Rose 1991; van Haselen died of atrial fibrillation, but this was not considered related to 2000), compared with carrier. There were insufficient data for treatment. quantitative analysis for any of these interventions. Event rates Conaghan 2013 (1395 participants) reported no serious adverse were generally below 10% in all treatment arms, and individ- events with ketoprofen 100 mg daily and three with the carrier ual studies did not indicate any major difference between topical alone, three serious events with ketoprofen 200 mg daily and four NSAID and carrier alone. with the carrier alone, and four with oral celecoxib 200 mg daily

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 18 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. and one with oral placebo. None were considered treatment re- Significantly fewer participants withdrew due to lack of efficacy lated. with topical diclofenac than with carrier; 3455 participants, RR NCT01980940 (48 participants) reported no serious adverse 0.59 (0.47 to 0.75), NNTp 26 (18 to 47) (Analysis 1.6), events for either etoricoxib 50 mg gel or carrier. There was no significant difference between topical ketoprofen Niethard 2005 (238 participants) reported one participant in the and carrier; 2885 participants, RR 1.1 (0.80 to 1.6), the NNTp carrier group who had a brain tumour. was not calculated (Analysis 2.5). Roth 2004 (397 participants) reported no serious adverse events We judged the quality of this evidence as moderate; there were in the topical ketoprofen arm, but one in the oral celecoxib arm adequate numbers of studies, participants, and events, and con- (myocardial infarction), and one in the carrier arm (angina). sistency of effect, but the size of the effect was very small for di- Rother 2013 (555 participants) reported three serious adverse clofenac (no effect for ketoprofen). events with ketoprofen 200 mg daily and four with carrier only. There were no significant differences between topical NSAID and One event with ketoprofen (headache) was possibly treatment re- carrier in any of the individual studies using other NSAIDs. lated. Simon 2009 (755 participants) reported no serious adverse events in the topical diclofenac arm, but one in the dimethyl sulphoxide 2. Topical NSAID versus any oral NSAID (DMSO) vehicle control arm (acute enteritis), four in the carrier without DMSO arm (anaemia, fractured hip, dislocated prosthetic hip, cerebrovascular event), and three in the oral diclofenac arm Participants with clinical success (leg cellulitis, unstable angina, transient ischaemic attack). Varadi 2013 (75 participants) reported no serious adverse events. Five studies contributed to this analysis, of which two also had a We judged the quality of this evidence for serious adverse events as placebo arm (Rother 2007; Simon 2009); 877 participants were very low; only one in three eligible studies reported this outcome treated with a topical NSAID and 858 with an oral NSAID. All and there were small numbers of events. There was no clear indi- studies used the double dummy method to maintain blinding. cation that serious adverse events were more common with topical • Dickson 1991 compared 1 g 0.5% piroxicam gel with oral NSAID than with carrier. ibuprofen tablet 400 mg, administered three times a day for four weeks. The response rate was 64% (75/117) with piroxicam gel and 60% (71/118) with ibuprofen tablets (response: PGE). Withdrawals due to adverse events • Rother 2007 compared 110 mg ketoprofen gel with oral Twenty-five studies (22 publications, one clinical registry report), celecoxib tablet 100 mg, administered twice daily for six weeks. with 7004 participants in comparisons with carrier, reported the The response rate was 46% (64/138) with ketoprofen gel and numbers of participants who withdrew due to an adverse event. 39% (51/132) with celecoxib tablets (response: PGE). Event rates ranged from 0% to 17% with active treatment, and • Simon 2009 compared 40 drops of 1.5% topical diclofenac from 0% to 16% with carrier, but were generally around 5%. solution with DMSO (Pennsaid®) administered four times daily There was a statistically significant difference between topical di- with slow-release oral diclofenac tablet 100 mg taken once daily, clofenac and carrier (3552 participants, RR 1.6 (1.1 to 2.1), NNH for 12 weeks. The response rate was 47% (73/154) with 51 (30 to 170) (Analysis 1.5), but not for ketoprofen and carrier diclofenac solution and 51% (77/151) with diclofenac tablets (2621 participants, RR 1.28 (0.92 to 1.8), the NNH was not cal- (response: ≥ 50% pain relief). culated) (Analysis 2.4). • Tugwell 2004 compared 50 drops of 1.5% topical We judged the quality of this evidence as moderate; there were diclofenac solution with DMSO (Pennsaid®) with oral adequate numbers of studies, participants, and events, and con- diclofenac tablet 50 mg administered three times a day for 12 sistency of effect, but the size of the effect was very small for di- weeks. The response rate was 66% (201/303) with diclofenac clofenac (no effect for ketoprofen). solution and 70% (210/301) with diclofenac tablets (response: There were no significant differences between topical NSAID and OMERACT-OARSI). carrier in any of the individual studies using other NSAIDs. • Zacher 2001 compared diclofenac Emulgel applied four times daily as a 10 cm ribbon of ointment with oral ibuprofen tablet 300 mg taken three times daily for three weeks. The Withdrawals due to lack of efficacy response rate was 40% (66/165) with diclofenac Emulgel and Twenty studies, with 6702 participants in comparisons with car- 34% (53/156) with ibuprofen tablets (response: ≥ 40% pain rier, reported on the numbers of participants who discontinued relief). treatment due to lack of efficacy. Event rates varied from 0% to 17% with active treatment, and from 0% to 26% with carrier, Although there were differences between studies in topical NSAID with higher rates often, but not always, associated with studies of used, oral NSAID comparator, and duration of study, we pooled longer duration. these studies in an exploratory analysis because knowing whether

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 19 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. there is any major difference in effect size between topical and oral NSAID is important. • The proportion of participants experiencing successful treatment with a topical NSAID was 55% (479/877, range 40% to 66%). • The proportion of participants experiencing successful treatment with oral NSAID was 54% (462/858, range 34% to 70%). • The RR of topical treatment compared with oral was 1.03 (0.95 to 1.1). • The NNT was not calculated (Analysis 3.1; Figure 5).

Figure 5. Forest plot of comparison: Topical NSAID versus oral NSAID, outcome: Clinical success.

We judged the quality of the evidence as very low; there were ade- We judged the quality of the evidence to be moderate. While the quate numbers of studies, participants and events, but the validity studies were well designed and conducted, and the number of of combining these studies is questionable, and there was inconsis- participants and events adequate, and with a consistent lack of tency in the results (I2 = 90%). The ﬁnding of fewer local adverse 2 effect (I = 34%), the analysis combined different topical and oral events with oral NSAID than with topical NSAID is plausible. preparations. One included study was not strictly blinded between topical ketoprofen and oral celecoxib, and so those results were not included Participants with systemic adverse events in this analysis, although results were consistent with there being Studies comparing a topical NSAID with an oral NSAID did not no difference between them (Conaghan 2013). report the total number of participants experiencing any systemic adverse event, but some did report the numbers in each treatment arm who experienced gastrointestinal adverse events. Gastroin- Participants with local adverse events testinal events commonly limit the use of oral NSAIDs and have Five studies contributed to this analysis (Dickson 1991; Roth been the driving force behind use of topical agents, so they are 2004; Sandelin 1997; Simon 2009; Tugwell 2004). A total of 846 considered here. Six studies contributed to this analysis (Dickson were treated with a topical NSAID and 805 with an oral NSAID. 1991; Roth 2004; Sandelin 1997; Simon 2009; Tugwell 2004; • The proportion of participants experiencing a local adverse Zacher 2001). A total of 1011 participants were treated with a event with a topical NSAID was 22% (182/846, range 3% to topical NSAID and 950 with an oral NSAID. 28%). • The proportion of participants experiencing a • The proportion of participants experiencing a local adverse gastrointestinal adverse event with a topical NSAID was 17% event with an oral NSAID was 5.8% (47/805, range 1% to 7%). (167/1011, range 5% to 35%). • The RR for a topical NSAID compared with oral NSAID • The proportion of participants experiencing a was 3.7 (2.8 to 5.1) (Analysis 3.2). gastrointestinal adverse event with an oral NSAID was 26% • The NNH was 6.4 (5.3 to 8.0). (248/950, range 9% to 48%).

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 20 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. • The RR for a topical NSAID compared with oral NSAID • The proportion of participants withdrawing due to lack of was 0.66 (0.56 to 0.77) (Analysis 3.3). efficacy with a topical NSAID was 7% (45/603, range 1% to • The NNTp was 10 (7.6 to 17). 10%). • The proportion of participants withdrawing due to lack of We judged the quality of the evidence as very low; there were ade- efficacy with oral NSAID was 3% (18/594, range 2% to 3%). quate numbers of studies, participants and events, but the validity • The RR for topical NSAID compared with oral NSAID of combining these studies is questionable, and there was some was 2.5 (1.5 to 4.2) (Analysis 3.5). inconsistency in the results (I2 = 62%). The finding of fewer sys- • The NNTp was 23 (14 to 52). temic adverse events with topical NSAID than with oral NSAID is plausible. We judged the quality of the evidence as very low; there were adequate numbers of studies, participants and modest numbers of events, but the validity of combining these studies is questionable. Participants with serious adverse events Rother 2007 (397 participants) reported no serious adverse events in the topical ketoprofen arm, but one in the oral celecoxib arm 3. Topical NSAID versus different topical NSAID (myocardial infarction), and one in the carrier arm (angina). Simon 2009 (755 participants) reported no serious adverse events in the topical diclofenac arm, but one in the DMSO carrier con- Participants with clinical success trol arm (acute enteritis), four in the carrier without DMSO arm Burgos 2001 compared flurbiprofen LAT patch 40 mg applied (anaemia, fractured hip, dislocated prosthetic hip, cerebrovascular twice daily with piketoprofen cream 1.8% applied three times event), and three in the oral diclofenac arm (leg cellulitis, unstable daily. There was a response rate of 79% (46/58) with flurbiprofen angina, transient ischaemic attack). and 65% (39/60) with piketoprofen. This study used an undefined Zacher 2001 (321 participants) reported ileus in one participant outcome of “any relief” as a measure of clinical success. who took oral ibuprofen. The event was judged to be unrelated to the study medication. There were too few events to draw any conclusions about serious Participants with local adverse events adverse events. Burgos 2001 reported that 3% (2/61) had experienced a local adverse event with flurbiprofen LAT patch 40 mg compared to 2% (1/60) with piketoprofen cream 1.8%. Withdrawals due to adverse events Six studies provided information about withdrawals due to adverse events (Dickson 1991; Rother 2007; Sandelin 1997; Simon 2009; Participants with systemic adverse events Tugwell 2004; Zacher 2001); 1011 participants were treated with There were no data for systemic adverse events in the study com- topical NSAID and 950 with oral NSAID. paring one topical NSAID with another. • The proportion of participants withdrawing due to an adverse event with a topical NSAID was 12% (121/1011, range 3% to 21%). Participants with serious adverse events • The proportion of participants withdrawing due to an There were no reported serious adverse events in the study com- adverse event with oral NSAID was 15% (140/950, range 1% to paring one topical NSAID with another. 25%). • The RR for topical NSAID compared with oral NSAID was 0.85 (0.68 to 1.1) (Analysis 3.4). Withdrawals due to adverse events • The NNTp was not calculated. Burgos 2001 reported that 2/64 participants withdrew due to an We judged the quality of the evidence as very low; there were adverse event with flurbiprofen LAT patch 40 mg compared with adequate numbers of studies, participants and modest numbers of 1/65 with piketoprofen cream 1.8%. events, but the validity of combining these studies is questionable. Withdrawals due to lack of efficacy Withdrawals due to lack of efficacy Burgos 2001 reported that 2/64 participants withdrew due to lack Only three studies provided information specifically about with- of efficacy with flurbiprofen LAT patch 40 mg compared with 3/ drawals due to lack of efficacy (Rother 2007; Simon 2009; Tugwell 65 with piketoprofen cream 1.8%. 2004); 603 participants were treated with topical NSAID and 594 There were too few data to draw any conclusions from comparisons with oral NSAID. of one topical NSAID with another.

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 21 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 4. Topical NSAID versus different topical treatment There were insufﬁcient data to comment on differences between topical treatments for systemic adverse events.

Participants with clinical success Three studies compared a topical NSAID with a different topical Participants with serious adverse events treatment. Widrig 2007 (198 participants) reported back trauma due to a fall • McCleane 2000 compared 2.5% piroxicam gel to 1% in one participant in the arnica treatment arm. glyceryl trinitrate (GTN) and a mixture containing 2.5% piroxicam gel with 1% GTN, applied three times daily for four Withdrawals due to adverse events weeks. There was a response rate of 3% (1/40) with piroxicam alone, 11% (4/36) with GTN, and 19% (7/37) with piroxicam/ • McCleane 2000 reported that 1/50 participants withdrew GTN mixture (response: ≥ 50% pain relief). due to an adverse event with 2.5% piroxicam cream, and none • van Haselen 2000 compared 1 g 0.5% piroxicam gel to 1 g with 1% GTN cream. SLR® homeopathic gel, containing Symphytum officinale • van Haselen 2000 reported that 1/89 participants withdrew (comfrey), Rhus toxicodendron (poison ivy), and Ledum palustre due to an adverse event with 0.5% piroxicam gel, compared to 1/ ® (marsh-tea), applied three times daily for four weeks. There was a 91 with SLR homeopathic gel. response rate of 22% (20/91) with piroxicam and 43% (38/89) • Widrig 2007 reported that 1/98 participants withdrew due with SLR® homeopathic gel (response: PGE). to an adverse event ibuprofen 5% gel, compared with 3/100 with • Widrig 2007 compared ibuprofen 5% gel with topical topical arnica 50% gel. arnica 50% gel applied as a 4 cm strip three times daily for three There were too few events to comment on differences between weeks. There was a response rate of 59% (50/85) with ibuprofen topical treatments for adverse event withdrawals. and 64% (57/89) with topical arnica, but this was a completer analysis (response: PGE). Withdrawals due to lack of efficacy There were insufficient data for meta-analysis for any of these comparisons. There were no reports specifically for withdrawals due to lack of efficacy in the three studies comparing a topical NSAID with a non-NSAID topical treatment. Participants with local adverse events • McCleane 2000 reported no local adverse events with any of the three topical treatments. • van Haselen 2000 reported 12% (11/91) had experienced a DISCUSSION local adverse reaction with 0.5% piroxicam gel, compared to 9% (7/89) with SLR® homeopathic gel. This update added data from only five studies, but increased the • Widrig 2007 reported only 7% (7/99) had experienced a total number of participants by 38%, from 7688 to 10,631. The local adverse reaction with both ibuprofen 5% gel and topical additional data came mainly from large studies of high reporting arnica 50% gel. quality using ketoprofen gel.

There were insufficient data to comment on differences between Summary of main results topical treatments for local adverse events. The results of this updated review are that diclofenac gel or solution has a modest benefit in longer-term studies of 6 to 12 weeks’ Participants with systemic adverse events duration. The NNT of 9.8 (95% confidence interval (CI) 7.1 to • McCleane 2000 reported that one participant in each arm 16) barely reached statistical significance (moderate quality evi- treated with piroxicam experienced a gastrointestinal event dence); shorter duration studies had a slightly lower, better, NNT (nausea, dyspepsia), and one in the placebo arm (nausea). of 7.5. For ketoprofen gel, with all ketoprofen doses combined, Seventeen participants treated with topical glyceryl trinitrate the NNT was 6.9 (5.4 to 9.3) (moderate quality evidence). Again, experienced nitrate headaches. this comparison only just reached statistical significance, and for • van Haselen 2000 reported that 5.5% (5/89 and 5/91) just the 200 mg dose no significant benefit was found over carrier. participants had experienced a systemic adverse reaction with It is worth mentioning that, for ketoprofen, one study produced 0.5% piroxicam gel and SLR® homeopathic gel. an opposite result, where carrier was better than carrier plus keto- • Widrig 2007 reported 8% (8/99) had experienced a profen (Figure 4). systemic adverse reaction with ibuprofen 5% gel and 14% (14/ It is also worth noting that the proportion of participants report- 100) with topical arnica 50% gel. ing significant pain relief with carrier (topical placebo) in both

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 22 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. these analyses was about 50% over 6 to 12 weeks, thus limiting the potential to demonstrate efficacy (Figure 6). It is also worth noting that there were no robust data for any other topical nonsteroidal anti-inflammatory drugs (NSAIDs) in any formulation, and that, in a limited number of comparisons, topical NSAID was not differentiated from oral NSAID. The frequency of local adverse events did not differ between topical NSAID and topical placebo carrier (moderate quality evidence), and although reporting of systemic adverse events was poor they also did not differ (very low quality evidence). This benign adverse event profile is why topical NSAIDs are recommended as first-line treatment for musculoskeletal conditions (Gaskell 2014; NICE 2014).

Figure 6. Placebo responses in topical NSAID studies for at least 50% pain intensity reduction after 12 weeks, compared with oral placebo from a pooled analysis and a single study with direct comparison with topical placebo.

The efficacy results in this update are not unlike those found for longer duration studies of diclofenac in the previous version of direct comparison (Conaghan 2013). this review, where the measured NNT then was 10 (7.3 to 17), Overall completeness and applicability of based on largely the same data. In the previous version, as here, evidence shorter duration studies produced lower, better, NNT values. The results for ketoprofen are new, and show that in the formulation There is a tension between pooling studies to produce analyses used there was no additional benefit for the topical NSAID over with larger numbers and the subsequent large increases in clini- the topical carrier. Suggestions that in these studies the topical cal and statistical heterogeneity on the one hand, and using the carrier had some analgesic effect of its own has to be judged by the approach of clinical homogeneity with subsequent smaller num- almost identical topical carrier (placebo) rates found in the topical bers of participants on the other. In this review, as in the previous diclofenac and topical ketoprofen studies. What is interesting is version, we have attempted as much as possible to analyse data by that the topical placebo carrier response rate in 6 to 12-week studies topical NSAID in a particular formulation. This should facilitate of around 50% is almost double that found for oral placebo in 12- decisions regarding choice of topical NSAID, since there is no in- week studies, where it was 22% to 27% for the outcome of at least herent reason why different NSAIDs and different formulations 50% pain intensity reduction over baseline (Figure 6), and 31% should perform equally. to 41% for the outcome of at least 30% pain intensity reduction While 11 different NSAIDs were investigated in our included (Moore 2010b). This at least raises the possibility that topical studies, there were sufficient data to make any judgement of clin- carriers confer some analgesic effect themselves, as suggested by ical utility for formulations of diclofenac and ketoprofen only. The most likely chronic musculoskeletal condition for which top-

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 23 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. ical NSAIDs are likely to be used is osteoarthritis, and the vast The results of this review are in substantial agreement with the pre- majority of participants in these studies had this condition (all vious version, and a number of previous systematic reviews of top- participants in more recent studies). Relevant age groups were well ical NSAIDs in chronic painful conditions (Biswal 2006; Mason represented, with mean age in individual studies ranging from 59 2004b; Moore 1998a; Towheed 2006), but do not agree with oth- to 65 years, and inclusion of individuals aged 90 years or more in ers (Bjordal 2007; Lin 2004). In 2004, Lin and colleagues had some studies. available only a few studies, and those with the longest duration (four weeks) used topical felbinac which showed no effect at any time; they were able to conclude only that the evidence supported Quality of the evidence topical NSAID effectiveness for two weeks (Lin 2004). Bjordal The quality of evidence on efficacy for longer duration studies (8 and colleagues also concluded, using very similar study informa- to 12 weeks) was good, with studies fulfilling all the criteria for tion, that topical NSAIDs had efficacy over 1 to 3 weeks (Bjordal good evidence in chronic pain trials (Moore 2010a; Moore 2012). 2007). The results presented here show clearly that high quality Shorter duration studies tended to be small, have less well defined large studies demonstrate efficacy of topical NSAIDs in 12-week outcomes, and lack clarity on imputation methods. Shorter dura- studies, with NNTs probably similar to those of oral NSAIDs. tion studies tended to have lower (better) NNT values, whetherfor A review of topical NSAIDs for osteoarthritis provides some ex- all topical NSAIDs or topical diclofenac alone. This differential perimental evidence on the mechanism of action and the concen- effect of study duration on efficacy estimate may reflect a number trations of drug found in different tissues following a period of of variables, particularly the likelihood of larger biases in shorter administration (Barthel 2010). Efficacy and safety are reviewed duration studies, but it also emphasises the need to concentrate in the most recent studies using diclofenac formulations that are on studies of longer duration for chronic painful conditions. Poor, licensed in the USA, in studies lasting 12 weeks, all of which are inconsistent reporting, together with low event rates, meant that included in this review. There was no quantitative analysis. evidence for adverse events was of very low quality. Another review looks at all topical treatments for osteoarthritis, again providing information on mechanisms of action and phar- macology (Altman 2011). There is a narrative review of trials using Potential biases in the review process various topical NSAIDs, all of which were considered for inclusion One potential bias is that clinical trials for topical NSAIDs may in this review; there is no quantitative analysis. not have been published. One previous review did find previously Other systematic reviews of safety of topical NSAIDs in acute unpublished trials (Moore 1998a), but a subsequent attempt that and chronic conditions agree that topical NSAIDs tend to be well included extensive contacts with pharmaceutical companies re- tolerated (Taylor 2011), as do longer-term open studies (Peniston vealed no additional data (Mason 2004a). While some old unpub- 2011; Shainhouse 2010). Results on adverse events in this review lished studies of topical NSAIDs in chronic painful conditions were similar to those in a pooled analysis of topical diclofenac may exist, they constitute an unknown number of studies and studies (Roth 2011). participants whose results are unknown, and are likely to remain unknown. Furthermore, their relevance to current clinical practice may be limited as better formulations are developed. New systems of trial registration mean that we know what recent studies have AUTHORS’ CONCLUSIONS been done or are ongoing; the number of studies and participants is known even if their results remain unknown. We identified a Implications for practice number of completed and ongoing studies in Clinicaltrials.gov. Although this review involved over 10,000 participants, we know For people with chronic musculoskeletal pain of additional studies with almost 7000 further participants, for Topical diclofenac and topical ketoprofen can provide good levels which we have no results. Perhaps not all would have been rel- of pain relief in knee osteoarthritis in people aged over 40 years, evant, but the fact that almost 6000 of these participants were but only in about 10% more people than with carrier. Adverse in studies concluded more than three years ago, and yet have no events are minimal with topical nonsteroidal anti-inflammatory results available, is something of a cause for concern. The reasons drugs (NSAIDs). might lie in the obvious difficulty in performing clinical trials in chronic musculoskeletal pain, as well as in protecting proprietary information. For clinicians Topical diclofenac and topical ketoprofen can provide good levels of pain relief in knee osteoarthritis, but only in about 10% more Agreements and disagreements with other people than with carrier. Adverse events are minimal with topi- studies or reviews cal NSAIDs. For this reason guidelines often suggest the use of

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 24 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. topical NSAIDs before oral NSAIDs, particularly in older people. There is little good evidence about other topical NSAIDs or topical There is little good evidence for topical NSAIDs in other chronic NSAIDs in other chronic conditions, and research in other forms musculoskeletal pain. of chronic pain might be appropriate.

Design For policy makers The design of the trials is generally good, and the knee osteoarthri- Topical NSAIDs are not associated with an increased incidence of tis model appears to be reliable and reproducible. Modern stud- local skin reactions compared with the inert carrier, and while the ies have ensured that participants entering the trials have at least carrier may cause mild, transient irritation, it is rarely troublesome. moderate pain, and this helps sensitivity to detect an analgesic Topical NSAIDs do not cause systemic (mainly gastrointestinal) response. Major changes to the design of these trials would not problems commonly seen with oral NSAIDs, making them par- appear to be needed, other than ensuring an adequate duration ticularly useful for individuals with osteoarthritis who are unable because shorter studies consistently report higher efﬁcacy. to tolerate oral administration, or for whom it is contraindicated. The efﬁcacy results we have are only applicable to knee osteoarthritis. Measurement (endpoints) A major issue is not in the measurement of pain, as most studies, especially modern ones, have used standard pain intensity and For funders pain relief scales. However, reporting of average pain changes is Topical diclofenac and topical ketoprofen preparations should be inadequate, and the use of responder analyses (at least 50% pain considered for treatment of chronic musculoskeletal painful con- intensity reduction, or patients experiencing mild or no pain) is ditions like knee osteoarthritis where there are no contraindica- preferred. tions, such as damaged skin. Formulations of topical NSAIDs are likely to change over time, Comparison between active treatments therefore the relevant trials performed and reported over 25 years ago must be limited and may be questionable. Funders might wish Indirect comparisons with carrier are probably as informative as to consider asking pharmaceutical companies without recent trial use of an active comparator, for which there are few. However, evidence for their products to produce it. comparisons between oral placebo and topical placebo (carrier only without NSAID) are an obvious target for future studies. Implications for research

General ACKNOWLEDGEMENTS The Oxford Pain Relief Trust, the NHS Cochrane Collaboration The general thrust of these findings is that gel formulations of Programme Grant Scheme, and the NIHR Biomedical Research topical diclofenac and topical ketoprofen can provide good levels Centre Programme provided support for the earlier review. of pain relief in patients with knee osteoarthritis, but only about 1 in 10 more will benefit with the topical NSAID than with topical The National Institute for Health Research (NIHR) is the largest placebo, or carrier. Response rates to topical placebo in relevant single funder of the Cochrane Pain, Palliative and Supportive longer duration studies appear to be substantially higher than with Care Review Group. Disclaimer: the views and opinions expressed oral placebo. The reason for this is not known, but the fact that herein are those of the authors and do not necessarily reflect those 50% of osteoarthritis patients can report very high levels of pain of the NIHR, National Health Service (NHS) or the Department relief without NSAID is not without importance. of Health

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A 12-week randomized study 2004;164:2017–23. of topical therapy with three dosages of ketoprofen in Transfersome® gel (IDEA-033) compared with the Rother 2007 {published data only} ketoprofen-free vehicle (TDT 064), in patients with Rother M, Lavins BJ, Kneer W, Lehnhardt K, Egbert osteoarthritis of the knee. Journal of Pain Research 2013;6: J, Mazgareanu S. Efficacy and safety of epicutaneous 743–53. [DOI: 10.2147/JPR.S51054] ketoprofen in Transfersome (IDEA-033) versus oral celecoxib and placebo in osteoarthritis of the knee: Link 1996 {published data only} multicentre randomised controlled trial. Annals of the Link R, Balint G, Pavlik G, Otto J, Krause W. Topical Rheumatic Diseases 2007;66:1178–83. [DOI: 10.1136/ treatment of soft tissue rheumatism and athletic injuries. ard.2006.065128] Effectiveness and tolerance of a new ketoprofengel [Topische Behandlungvon Weichteil–rheumatismus und Rother 2013 {published data only} Sportverletzungen. Wirksamkeitund Verträglichkeit eines Rother M, Conaghan PG. A randomized, double-blind, neuen Ketoprofengels]. Fortschritte der Medizin 1996;114: phase III trial in moderate osteoarthritis knee pain 311–4. comparing topical ketoprofen gel with ketoprofen-free McCleane 2000 {published data only} gel. Journal of Rheumatology 2013;40(10):1742–8. [DOI: McCleane G. The addition of piroxicam to topically 10.3899/jrheum.130192] applied glyceryl trinitrate enhances its analgesic effect in Sandelin 1997 {published data only} musculoskeletal pain: a randomised, double-blind, placebo- Sandelin J, Harilainen A, Crone H, Hamberg P, Forsskahl controlled study. Pain Clinic 2000;12:113–6. B, Tamelander G. Local NSAID gel (eltenac) in the NCT01980940 {published data only} treatment of osteoarthritis of the knee. A double blind Merck Sharp, Dohme Corp (Sponsor). A study to assess the study comparing eltenac with oral diclofenac and placebo single dose pharmacokinetics of two and proof of efficacy of gel. Scandinavian Journal of Rheumatology 1997;26:287–92. one new etoricoxib gel formulation in osteoarthritis patients. www.clinicaltrials.gov/ct2/show/NCT01980940 (accessed Simon 2009 {published data only} 19 November 2015) 2015. [CTG: NCT01980940] Simon LS, Grierson LM, Naseer Z, Bookman AA, Shainhouse JZ. Efficacy and safety of topical diclofenac Niethard 2005 {published data only} containing dimethyl sulfoxide (DMSO) compared with Niethard FU, Gold MS, Solomon GS, Liu JH, Unkauf those of topical placebo, DMSO vehicle and oral diclofenac M, Albrecht HH, et al. Efficacy of topical diclofenac for knee osteoarthritis. Pain 2009;143(3):238–45. [DOI: diethylamine gel in osteoarthritis of the knee. Journal of 10.1016/j.pain.2009.03.008] Rheumatology 2005;32(12):2384–92. Ottillinger 2001 {published data only} Tugwell 2004 {published data only} Ottillinger B, Gomor B, Michel BA, Pavelka K, Beck W, Tugwell PS, Wells GA, Shainhouse JZ. Equivalence study Elsasser U. Efficacy and safety of eltenac gel in the treatment of a topical diclofenac solution (Pennsaid) compared with of knee osteoarthritis. Osteoarthritis Cartilage 2001;9: oral diclofenac in symptomatic treatment of osteoarthritis 273–80. [DOI: 10.1053/joca.2000.0385] of the knee: a randomized controlled trial. Journal of Rheumatology 2004;31(10):2002–12. Poul 1993 {published data only} Poul J, West J, Buchanan N, Grahame R. Local action van Haselen 2000 {published data only} transcutaneous flurbiprofen in the treatment of soft tissue van Haselen RA, Fisher PA. A randomized controlled trial rheumatism. British Journal of Rheumatology 1993;32: comparing topical piroxicam gel with a homeopathic gel in 1000–03. [DOI: 10.1093/rheumatology/32.11.1000] osteoarthritis of the knee. Rheumatology 2000;39:714–9.

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 27 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Varadi 2013 {published data only} Ginsberg 1991 {published data only} Varadi G, Zhu Z, Blattler T, Hosle M, Loher A, Pokorny Ginsberg F, Famaey JP. Double-blind, randomized cross- R, et al. Randomized clinical trial evaluating transdermal over study of the percutaneous efficacy and tolerability of a Ibuprofen for moderate to severe knee osteoarthritis. Pain topical indomethacin spray versus placebo in the treatment Physician 2013;16(6):E749–62. [PUBMED: 24284856] of tendinitis. Journal of Internal Medicine 1991;19:131–6. Widrig 2007 {published data only} Mattara 1994 {published data only} Widrig R, Suter A, Saller R, Melzer J. Choosing between Mattara L, Trotta F, Biasi D, Cervetti R. Evaluation of the NSAID and arnica for topical treatment. Rheumatology efficacy and tolerability of a new locally acting preparation International 2007;27:585–91. [DOI: 10.1007/ of flurbiprofen in scapulohumeral periarthritis. European s00296-007-0304-y] Journal of Rheumatology and Inflammation 1994;4:15–20. Zacher 2001 {published data only} Peniston 2011 {published data only} Zacher J, Burger KJ, Farber L, Grave M, Abberger H, Peniston JH, Gold MS, Alwine LK. An open-label, long- Bertsch K. Topical diclofenac versus oral ibuprofen: a double term safety and tolerability trial of diclofenac sodium 1% blind, randomized clinical trial to demonstrate efficacy and gel in patients with knee osteoarthritis. The Physician tolerability in patients with activated osteoarthritis of the and Sportsmedicine 2011;39(3):31–8. [DOI: 10.3810/ finger joints (Heberden and/or Bouchard arthritis). Aktuelle psm.2011.09.1918] Rheumatologie 2001;26:7–14. Rovensky 2001 {published data only} References to studies excluded from this review Rovensky J, Micekova D, Gubzova Z, Fimmers R, Lenhard G, Vogtle-Junkert U, et al. Treatment of knee osteoarthritis Allegrini 2009 {published data only} with a topical non-steroidal antiinflammatory drug. Results Allegrini A, Nuzzo L, Pavone D, Tavella-Scaringi A, of a randomized, double-blind, placebo-controlled study on Giangreco D, Bucci M, et al. Efficacy and safety of the efficacy and safety of a 5% ibuprofen cream. Drugs piroxicam patch versus piroxicam cream in patients with Under Experimental and Clinical Research 2001;27:209–21. lumbar osteoarthritis. A randomized, placebo-controlled Tiso 2010 {published data only} study. Arzneimittel-Forschung 2009;59(8):403–9. Tiso RL, Tong-Ngork S, Fredlund KL. Oral versus topical Di Rienzo Businco 2004 {published data only} ibuprofen for chronic knee pain: a prospective randomised Di Rienzo Businco L, Di Rienzo Businco A, D’Emilia pilot study. Pain Physician 2010;13:457–67. M, Lauriello M, Coen Tirelli G. Topical versus systemic Trnavský 2004 {published data only} diclofenac in the treatment of temporo-mandibular Trnavský K, Fischer M, Vögtle-Junkert U, Schreyger F. joint dysfunction symptoms [Confronto diclofenac Efficacy and safety of 5% ibuprofen cream treatment in topico versus sistemico nel trattamento dei sintomi da knee osteoarthritis. Results of a randomized, double-blind, disfunzione dell’articolazione temporo–mandibolare]. Acta placebo-controlled study. Journal of Rheumatology 2004;31 Otorhinolaryngologica Italica 2004;24(5):279–83. (3):565–72. Doi 2010 {published data only} Underwood 2008 {published data only} Doi T, Akai M, Fujino K, Hoshino Y, Iwaya T, Sunami Y. Underwood M, Ashby D, Carnes D, Castelnuovo E, Cross Effect of nonsteroidal anti-inflammatory drug plasters for P, Harding G, et al. Topical or oral ibuprofen for chronic knee osteoarthritis in Japanese: a randomised controlled knee pain in older people. The TOIB study. Health trial. Modern Rheumatology 2010;20:24–33. Technology Assessment 2008;12:22. Fotiades 1976 {published data only} Verkleij 2015 {published data only} Fotiades P, Bach GL. The effect of a flufenamic acid Verkleij SP, Luijsterburg PA, Willemsen SP, Koes BW, containing ointment in various rheumatic diseases [Wirkung Bohnen AM, Bierma-Zeinstra SM. Effectiveness of einer flufenaminsaurehaltigen Salbe bei verschiedenen diclofenac versus paracetamol in knee osteoarthritis: a rheumatischen Erkrankungen]. Fortschritte der Medizin randomised controlled trial in primary care. British Journal 1976;94:1036–8. of General Practice 2015;65(637):e530–7. [DOI: 10.3399/ Galer 2010 {published data only} bjgp15X686101] Galer BS. A comparative subjective assessment study of Vitali 1980 {published data only} Pennsaid and Voltaren gel, two topical formulations of Vitali G. Controlled clinical experiment with the topical diclofenac sodium. Pain Practice 2011;11(3):252–60. use of 2-(3-benzoyl-phenyl) propionic acid at 3 different Geller 1980 {published data only} concentrations [Sperimentazione clinica controllata Geller O. Comparison of a salicylate heparin gel with a sull’impiego topicodell’acido 2–(3–benzoil–fenil) monosubstance preparation. Results of a double blind proprionico a tre diverse concentrazioni]. Clinical cross over study [Vergleich eines Salizylat/Heparin–Gels Therapeutics 1980;94:257–73. mit einemMono–substanzpräparat. Ergebnisse einer Doppelblindcross–over–Studie.]. Munchener Medizinische References to studies awaiting assessment Wochenschrift 1980;122:1231–2.

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 28 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Bohlooli 2012 {published data only} Bjordal 2007 Bohlooli S, Jastan M, Nakhostin-Roohi B, Mohammadi Bjordal JM, Klovning A, Ljunggren AE, Slørdal L. Short- S, Baghaei Z. A pilot double-blinded, randomized, term efficacy of pharmacotherapeutic interventions in clinical trial of topical virgin olive oil versus piroxicam osteoarthritic knee pain: a meta-analysis of randomised gel in osteoarthritis of the knee. Journal of Clinical placebo-controlled trials. European Journal of Pain 2007;11 Rheumatology 2012;18(2):99–101. [DOI: 10.1097/ (2):125–38. [DOI: 10.1016/j.ejpain.2006.02.013] RHU.0b013e31824a47b5] Conaghan 2014 Niempoog 2012 {published data only} Conaghan PG, Bijlsma JW, Kneer W, Wise E, Kvien TK, Niempoog S, Siriarchavatana P,Kajsongkram T. The efficacy Rother M. Drug-free gel containing ultra-deformable of Plygersic gel for use in the treatment of osteoarthritis phospholipid vesicles (TDT 064) as topical therapy for the of the knee. Journal of the Medical Association of Thailand treatment of pain associated with osteoarthritis: a review 2012;95 Suppl 10:S113–9. [PUBMED: 23451449] of clinical efficacy and safety. Current Medical Research and Opinion 2014;30(4):599–611. [DOI: 10.1185/ References to ongoing studies 03007995.2013.860018] Cook 1995 NCT01377038 {unpublished data only} Cook RJ, Sackett DL. The number needed to treat: a Phillips K (Principal investigator). Central pain clinically useful measure of treatment effect. BMJ 1995; mechanisms in osteoarthritis: a randomized, double- 310:452–4. blind, crossover study to evaluate the effectiveness of topical diclofenac versus duloxetine for chronic Dechartres 2013 osteoarthritis pain. www.clinicaltrials.gov/ct2/show/record/ Dechartres A, Trinquart L, Boutron I, Ravaud P. Influence NCT01377038 (accessed 19 November 2015) 2015. of trial sample size on treatment effect estimates: meta- [CTG: NCT01377038] epidemiological study. BMJ 2013;346:f2304. [DOI: 10.1136/bmj.f2304] NCT02068859 {published data only} FPR Specialty Pharmacy. Treatment of knee pain with Derry 2012b topical diclofenac cream 8% or diclofenac gel 1%. Derry S, Moore RA. Topical capsaicin (low concentration) www.clinicaltrials.gov/ct2/show/NCT02068859 (accessed for chronic neuropathic pain in adults. Cochrane Database 19 November 2015) 2014. [CTG: NCT02068859] of Systematic Reviews 2012, Issue 9. [DOI: 10.1002/ NCT02121002 {published data only} 14651858.CD010111] Prayag Shah, MD (Study director). A multi-center, Derry 2013 double-blind, vehicle-controlled, parallel-group study Derry S, Sven-Rice A, Cole P, Tan T, Moore RA. Topical comparing a generic diclofenac sodium topical gel, 1% capsaicin (high concentration) for chronic neuropathic pain to Voltaren® gel (diclofenac sodium topical gel) 1% in in adults. Cochrane Database of Systematic Reviews 2013, the treatment of subjects with osteoarthritis of the knee. Issue 2. [DOI: 10.1002/14651858.CD007393.pub3] www.clinicaltrials.gov/ct2/show/NCT02121002 (accessed Derry 2014 19 November 2015) 2015. [CTG: NCT02121002] Derry S, Matthews PR, Wiffen PJ, Moore RA. Additional references Salicylate-containing rubefacients for acute and chronic musculoskeletal pain in adults. Cochrane Database of Altman 2011 Systematic Reviews 2014, Issue 11. [DOI: 10.1002/ Altman RD, Barthel HR. Topical therapies for 14651858.CD007403.pub3] osteoarthritis. Drugs 2011;71(10):1259–79. [DOI: Derry 2015 10.2165/11592550-000000000-00000] Derry S, Moore RA, Gaskell H, McIntyre M, Wiffen PJ. Bandolier 2005 Topical NSAIDs for acute musculoskeletal pain in adults. Anon. Topical analgesics: a review of reviews and a Cochrane Database of Systematic Reviews 2015, Issue 6. bit of perspective. www.medicine.ox.ac.uk/bandolier/ [DOI: 10.1002/14651858.CD007402.pub3] Extraforbando/Topextra3.pdf (accessed 18 November 2015) Dougados 2000 2005. Dougados M, Leclaire P, van der Heijde D, Bloch DA, Barthel 2010 Bellamy N, Altman RD. Response criteria for clinical Barthel HR, Axford-Gatley RA. Topical nonsteroidal anti- trials on osteoarthritis of the knee and hip: a report of inflammatory drugs for osteoarthritis. Postgraduate Medicine the Osteoarthritis Research Society International Standing 2010;122(6):98–106. [DOI: 10.3810/pgm.2010.11.2227] Committee for Clinical Trials response criteria initiative. Biswal 2006 Osteoarthritis Cartilage 2000;8(6):395–403. [DOI: Biswal S, Medhi B, Pandhi P. Longterm efficacy of topical 10.1053/joca.2000.0361] nonsteroidal antiinflammatory drugs in knee osteoarthritis: Evans 1995 meta-analysis of randomized placebo controlled clinical Evans JM, McMahon AD, McGilchrist MM, White G, trials. Journal of Rheumatology 2006;33(9):1841–4. Murray FE, McDevitt DG, et al. Topical non-steroidal anti-

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 29 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. inflammatory drugs and admission to hospital for upper Mason 2004b gastrointestinal bleeding and perforation: a record linkage Mason L, Moore RA, Edwards JE, Derry S, McQuay case-control study. BMJ 1995;311(6996):22–6. HJ. Topical NSAIDs for chronic musculoskeletal pain: systematic review and meta-analysis. BioMed Central Fitzgerald 2001 Musculoskeletal Disorders 2004;5:28. [DOI: 10.1186/ Fitzgerald GA, Patrono C. The coxibs, selective 1471-2474-5-28] inhibitors of cyclooxygenase-2. New England Journal of Medicine 2001;345(6):433–42. [DOI: 10.1056/ McPherson 2013 NEJM200108093450607] McPherson ML, Cimino NM. Topical NSAID formulations. Pain Medicine 2013;14 Suppl 1:S35–9. Gaskell 2014 [DOI: 10.1111/pme.12288] Gaskell H, Derry S, Moore RA. Treating chronic non- Moore 1998a cancer pain in older people--more questions than answers?. Maturitas 2014;79(1):34–40. [DOI: 10.1016/ Moore RA, Tramèr MR, Carroll D, Wiffen PJ, McQuay HJ. Quantitative systematic review of topically applied non- j.maturitas.2014.06.013] steroidal anti-inflammatory drugs. BMJ (Clinical Research GRADEpro GDT 2015 [Computer program] Ed) 1998;316(7128):333–8. McMaster University (developed by Evidence Prime, Inc.). Moore 1998b GRADEpro Guideline Development Tool [Software]. Moore RA, Gavaghan D, Tramèr MR, Collins SL, McQuay Available from www.gradepro.org (accessed 11 February HJ. Size is everything - large amounts of information are 2016), 2015. needed to overcome random effects in estimating direction Haroutiunian 2010 and magnitude of treatment effects. Pain 1998;78(3): Haroutiunian S, Drennan DA, Lipman AG. Topical NSAID 209–16. [DOI: 10.1016/S0304-3959(98)00140-7] therapy for musculoskeletal pain. Pain Medicine 2010;11 Moore 2008a (4):535–49. [DOI: 10.1111/j.1526-4637.2010.00809.x] Moore RA, Derry S, McQuay HJ. Topical agents in the Higgins 2011 treatment of rheumatic pain. Rheumatic Disease Clinics Higgins JPT, Green S (editors). Cochrane Handbook of North America 2008;34(2):415–32. [DOI: 10.1016/ for Systematic Reviews of Interventions Version 5.1.0 j.rdc.2008.03.006] [updated March 2011]. The Cochrane Collaboration, Moore 2008b 2011. Available from www.cochrane-handbook.org. Moore RA, Barden J, Derry S, McQuay HJ. Managing potential publication bias. In: McQuay HJ, Kalso E, Jadad 1996a Moore RA editor(s). Systematic Reviews in Pain Research: Jadad AR, Carroll D, Moore A, McQuay H. Developing a Methodology Refined. Seattle: IASP Press, 2008:15–24. database of published reports of randomised clinical trials in [ISBN: 978–0–931092–69–5] pain research. Pain 1996;66(2-3):239–46. [DOI: 10.1016/ 0304-3959(96)03033-3] Moore 2010a Moore RA, Eccleston C, Derry S, Wiffen P,Bell RF, Straube Jadad 1996b S, et al. “Evidence” in chronic pain--establishing best Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds practice in the reporting of systematic reviews. Pain 2010; DJ, Gavaghan DJ, et al. Assessing the quality of reports of 150(3):386–9. [DOI: 10.1016/j.pain.2010.05.011] randomized clinical trials: is blinding necessary?. Controlled Clinical Trials 1996;17:1–12. [DOI: 10.1016/0197-2456 Moore 2010b (95)00134-4] Moore RA, Moore OA, Derry S, Peloso PM, Gammaitoni AR, Wang H. Responder analysis for pain relief and L’Abbé 1987 numbers needed to treat in a meta-analysis of etoricoxib L’Abbé KA, Detsky AS, O’Rourke K. Meta-analysis in osteoarthritis trials: bridging a gap between clinical trials clinical research. Annals of Internal Medicine 1987;107: and clinical practice. Annals of the Rheumatic Diseases 2010; 224–33. 69(2):374–9. [DOI: 10.1136/ard.2009.107805] Lin 2004 Moore 2012 Lin J, Zhang W, Jones A, Doherty M. Efficacy of topical Moore RA, Straube S, Eccleston C, Derry S, Aldington D, non-steroidal anti-inflammatory drugs in the treatment Wiffen P, et al. Estimate at your peril: Imputation methods of osteoarthritis: meta-analysis of randomised controlled for patient withdrawal can bias efficacy outcomes in chronic trials. BMJ 2004;329(7461):324. [DOI: 10.1136/ pain trials using responder analyses. Pain 2012;153(2): bmj.38159.639028.7C] 265–8. [DOI: 10.1016/j.pain.2011.10.004] Mason 2004a Moore 2013 Mason L, Moore RA, Edwards JE, Derry S, McQuay Moore RA, Straube S, Aldington D. Pain measures and HJ. Topical NSAIDs for acute pain: a meta-analysis. cut-offs - ’no worse than mild pain’ as a simple, universal BioMed Central Family Practice 2004;5:10. [DOI: 10.1186/ outcome. Anaesthesia 2013;68(4):400–12. [DOI: 10.1111/ 1471-2296-5-10] anae.12148]

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 30 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Morris 1995 Shainhouse 2010 Morris JA, Gardner MJ. Calculating confidence intervals Shainhouse JZ, Grierson LM, Naseer Z. A long- for relative risk, odds ratios and standardised ratios and term, open-label study to confirm the safety of topical rates. In: Gardner MJ, Altman DG editor(s). Statistics with diclofenac solution containing dimethyl sulfoxide in the Confidence - Confidence Intervals and Statistical Guidelines. treatment of the osteoarthritic knee. American Journal London: British Medical Journal, 1995:50–63. of Therapeutics 2010;17(6):566–76. [DOI: 10.1097/ NICE 2008 MJT.0b013e3181d169b5] National Collaborating Centre for Chronic Conditions. Taylor 2011 Osteoarthritis: National Clinical Guideline for Care and Taylor RS, Fotopoulos G, Maibach H. Safety profile of Management in Adults. London: Royal College of topical diclofenac: a meta-analysis of blinded, randomized, Physicians, 2008. [ISBN: 978–1–86016–329–6] controlled trials in musculoskeletal conditions. Current NICE 2014 Medical Research and Opinion 2011;27(3):605–22. [DOI: Osteoarthritis. Care and management in adults. NICE 10.1185/03007995.2010.550606] clinical guideline 177. nice.org.uk/guidance/cg177/ evidence 2014. [ISBN: 978–1–4731–0426–6] Towheed 2006 Towheed TE. Pennsaid therapy for osteoarthritis of the Nüesch 2010 knee: a systematic review and meta-analysis of randomized Nüesch E, Trelle S, Reichenbach S, Rutjes AW, Tschannen controlled trials. Journal of Rheumatology 2006;33(3): B, Altman DG, et al. Small study effects in meta-analyses 567–73. [DOI: 10.2147/JPR.S20965] of osteoarthritis trials: meta-epidemiological study. BMJ 2010;341:c3515. [DOI: 10.1136/bmj.c3515] Tramer 1997 PaPaS 2012 Tramer MR, Reynolds DJ, Moore RA, McQuay HJ. Impact PaPaS author and referee guidance. http:// of covert duplicate publication on meta-analysis: a case papas.cochrane.org/papas-documents (accessed 9 March study. BMJ 1997;315(7109):635–40. 2015). Vos 2012 PCA 2015 Vos T, Flaxman AD, Naghavi M, Lozano R, Michaud Prescribing and Medicines Team, Health and Social Care C, Ezzati M, et al. Years lived with disability (YLDs) for Information Centre. Prescription Cost Analysis, England 1160 sequelae of 289 diseases and injuries 1990-2010: a 2014. www.hscic.gov.uk/catalogue/PUB17274/pres-cost- systematic analysis for the Global Burden of Disease Study anal-eng-2014-rep.pdf (accessed 11 February 2016). 2010. Lancet 2012;380(9859):2163–96. [DOI: 10.1016/ The NHS Information Centre, 2015:309–312. [ISBN: S0140-6736(12)61729-2] 978–1–78386–365–5] RevMan 2014 [Computer program] References to other published versions of this review The Nordic Cochrane Centre, The Cochrane Collaboration. Review Manager (RevMan). Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, Derry 2012a 2014. Derry S, Moore RA, Rabbie R. Topical NSAIDs for Roth 2011 chronic musculoskeletal pain in adults. Cochrane Database Roth SH, Fuller P. Diclofenac topical solution compared of Systematic Reviews 2012, Issue 9. [DOI: 10.1002/ with oral diclofenac: a pooled safety analysis. Journal of Pain 14651858.CD007400.pub2] Research 2011;4:159–67. [DOI: 10.2147/JPR.S20965] ∗ Indicates the major publication for the study

Characteristics of included studies [ordered by study ID]

102-93-1

Methods R, DB, PC, parallel group Assessment at baseline, 2, 4, 6 weeks

Participants OA knee (diagnosed by standard radiological criteria and interview) with ≥ moderate pain within previous 2 weeks N = 122 No further demographic details provided

Interventions (1) Diclofenac solution (with 45.5% DMSO) (2) Control (with 45.5% DMSO) (3) Placebo (with 4.55% DMSO) Measured dose (4 x 40 drops, about 1 mL) applied 4 times daily using applicator pad, for 6 weeks Number of participants in each group not reported 2-week washout if confounding medication had been used

Outcomes Daily global comparison (better, same, worse) for pain at rest, pain on motion, nocturnal pain Adverse events: local, systemic

Notes Oxford Quality Score: R2, DB1, W0. Total = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Unclear risk Not described bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Imputation: N/A - no useable efﬁcacy data. All outcomes Total attrition < 10%

Study duration Low risk 6 weeks

Size High risk < 50 participants per treatment arm

Methods R, DB, PC, parallel group Assessment at baseline, 2, 4, 6 weeks

Participants OA hand (diagnosed by standard radiological criteria and interview) with ≥ moderate (but not extreme) pain N = 203 (195 for ITT) No further demographic details provided

Interventions (1) Diclofenac solution (with 45.5% DMSO), n = 48 (2) Control (with 45.5% DMSO), n = 47 (3) Diclofenac solution (with 2.3% DMSO), n = 50 (4) Placebo (with 2.3% DMSO), n = 50 Measured dose (to maximum 40 drops/hand) applied 4 times daily for 6 weeks Rescue medication: paracetamol (500 mg to maximum 3 g daily) except in 24 h before assessments

Outcomes AUSCAN LK3 pain dimension PGE: 5-point scale Withdrawals

Notes Oxford Quality Score: R1, DB1, W1. Total = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Unclear risk Not described bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Imputation: N/A - no useable efﬁcacy data. All outcomes Total attrition < 10%

Study duration Low risk 6 weeks

Size High risk < 50 participants in 2 treatment arms, 50 in other 2

Methods R, DB, PC, parallel group Assessment at baseline, 1, 2, 4, 6, 8 weeks

Participants OA hand (ACR criteria) for ≥ 12 months, use of NSAID for ≥ 1 episode of pain. Flare required following NSAID washout (≥ 7 days) if applicable N = 385 M 89, F 296 Mean age 64 years (range 40 to 92) Baseline pain ≥ 40 mm

Interventions (1) Diclofenac sodium gel 1% (Voltaren) with vehicle, n = 198 (2) Placebo gel (vehicle carrier) n = 187 Measured dose (2 g) of gel applied with gentle massage 4 times daily for 8 weeks Rescue medication: paracetamol 500 mg (to maximum 4 g daily) but not for 36 h before assessment

Outcomes OARSI response in dominant hand at 8 weeks AUSCAN score for the dominant hand PGE: 5-point scale (responder = “very good” or “excellent”) Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1. Total = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk “identical in appearance, smell, and tex- bias) ture” All outcomes

Incomplete outcome data (attrition bias) Low risk Worst observation carried forward, adverse All outcomes event withdrawal low, “other” attrition < 10%

Study duration Low risk 8 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Methods R, DB, PC, parallel groups Assessed at baseline, 6 weeks

Participants Primary OA of at least 1 knee A ﬂare of pain after withdrawal of prior therapy with either NSAID or paracetamol N = 216 (212 for efﬁcacy) M 94, F 122 Mean age 65 years Mean baseline pain 13/20

Interventions (1) Diclofenac sodium 1.5% (with DMSO, Pennsaid®), n = 107 (2) Placebo (vehicle carrier), n = 109 Medication (40 drops) applied around affected knee (front, back, and sides) without massage, 4 times daily for 6 weeks Rescue medication: paracetamol (maximum 1500 mg daily) except during washout and week before ﬁnal assessment

Outcomes ≥ 50% PR (provided by author) PGE: 5-point scale (responder = “good” or “very good”) OMERACT-OARSI responder Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “computer-generated” bias)

Allocation concealment (selection bias) Low risk “randomisation schedule was concealed from the investigators, their support staff, study participants and the sponsor’s clinical research personnel”

Blinding (performance bias and detection Low risk “two study solutions were identical clear, bias) colourless liquids packaged in opaque bot- All outcomes tles”

Incomplete outcome data (attrition bias) Low risk Primary outcome using BOCF imputa- All outcomes tion supplied by author. “Other” attrition greater in placebo arm (11%)

Study duration Low risk 6 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Methods R, DB, AC, parallel groups Assessed at baseline, 7, 14 days

Participants Finger or knee arthritis, or shoulder tendinitis N = 50 M/F not reported Age not reported Baseline pain not reported

Interventions (1) Diclofenac (Voltaren Emulgel), n = 25 (2) Indomethacin (Indocid) gel, n = 25 Gel applied twice daily with gently rubbing, for 2 weeks

Outcomes No dichotomous efﬁcacy outcomes Improvement in composite of 4 scales (mean) Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1. Total = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Unclear risk “tubes were presented in the same outer bias) packaging, bearing a serial number so as to All outcomes randomize the allocation of treatments”

Incomplete outcome data (attrition bias) Unclear risk N/A - no useable efﬁcacy data All outcomes

Study duration High risk 2 weeks

Size High risk < 50 participants per treatment arm

Baraf 2011

Methods 3 separate studies, combined for analysis. R, DB, PC, parallel groups Assessment at baseline, 1, 4, 8, 12 weeks

Participants OA knee, with radiographic conﬁrmation, according to ACR criteria, and ≥ 6 months after symptom onset. Daily pain requiring treatment for ≥ 2 weeks in previous month N = 1426 (ITT = 1424) M/F not reported

Mean age not reported: 25 to 64 years, N = 888, ≥ 65 years, N = 538 Baseline pain on movement ≥ 50/100 mm Subpopulation who had no change or increase in baseline pain during washout (similar to ”ﬂare“ population), N = 976

Interventions (1) Diclofenac sodium gel 1%, n = 721 (2) Placebo gel (vehicle only), n = 705 Measured dose (4 g) of gel applied around knee 4 times daily for 12 weeks. Participants instructed to wait ≥ 10 minutes before dressing and to avoid vigorous exercise or bathing/ showering within 1 h Rescue: paracetamol (maximum 4 g daily) but not within 24 h of assessments

Outcomes OARSI response in treated knee (using pain on movement) at 12 weeks OARSI response in treated knee (using WOMAC pain index) at 12 weeks WOMAC subscales: pain (0 to 20) and physical function (0 to 68) (mean data) Pain on movement: 100 mm VAS (mean data) PGE: 5-point scale (mean data) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk ”central randomization list generated by bias) manufacturer

Allocation concealment (selection bias) Low risk Remote allocation; “all site and sponsor personnel, and patients, were blinded as to treatment allocation until after the database was locked and the statistical analysis plan was ﬁnalized”

Blinding (performance bias and detection Low risk Gels were “identical in appearance, feel, bias) and smell” All outcomes

Incomplete outcome data (attrition bias) Unclear risk Imputation: BOCF for early discontinua- All outcomes tion. “Other” attrition higher in placebo group (12%)

Study duration Low risk 12 weeks

Size Low risk > 200 participants per treatment group

Methods R, DB, PC, parallel group Assessed at baseline, 7, 14 days

Participants Extra-articular rheumatic disorders N = 281 M 98, F 183 Mean age 53 years (18 to 79 years) Baseline pain moderate or severe at rest or with movement

Interventions (1) Felbinac gel 3%, n = 142 (2) Placebo gel, n = 139 Gel (1 g) applied 3 times daily without massage, for up to 2 weeks Rescue medication: paracetamol Physiotherapy could be continued without change

Outcomes Any improvement: (responder = improved) Adverse events

Notes Oxford Quality Score: R1, DB2, W0. Total = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk “identical appearance” bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described All outcomes

Study duration High risk 2 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Bookman 2004

Methods R, DB, PC, parallel groups Assessed at baseline, 1, 2, 3, 4 weeks, with patients daily assessment of pain, function, stiffness, and weekly PGE

Participants OA knee (no ﬂare required), radiographically conﬁrmed and with ≥ moderate pain for 2 weeks. Worst affected knee designated as study knee N = 248

M 91, F 157 Mean age 62 years At least moderate pain, mean baseline pain > 9/20

Interventions (1) Diclofenac solution 1.5% in DMSO 45.5% (Pennsaid®), n = 84 (2) Carrier with DMSO 45.5%, n = 80 (2) Carrier with DMSO 4.55%, n = 84 Medication (40 drops) applied around affected knee (front, back, and sides), without massage, 4 times daily for 4 weeks Rescue medication: paracetamol (maximum 3 g daily) except during 24 h before baseline and ﬁnal assessments

Outcomes ≥ 50% PR (provided by authors) WOMAC sub scales: pain (0 to 20), pain on walking (0 to 4), and physical function (0 to 68) (mean data) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “computer-generated” bias)

Allocation concealment (selection bias) Low risk “sequence concealed from anyone directly involved in conducting the study until ﬁ- nal data lock”. Study kits labelled independently

Blinding (performance bias and detection Low risk “study solutions were identical, clear bias) colourless liquids in opaque bottles”. Small All outcomes amount of DMSO in placebo solution provided characteristic smell

Incomplete outcome data (attrition bias) Low risk Imputation: All outcomes primary outcome using BOCF imputation supplied by author. “Other” attrition low and equal between groups

Study duration Unclear risk 4 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Methods R, DB, PC, parallel groups Assessed at baseline, 4, 7, 14 days

Participants Symptomatic knee osteoarthritis N = 103 M 43, F 60 Mean age 64 years Baseline pain ≥ 40 mm

Interventions (1) Diclofenac (DHEP 1.3%) patch, n = 51 (2) Placebo patch, n = 52 Patch applied topically twice daily for 2 weeks Rescue medication: paracetamol 500 mg (maximum 2 g daily)

Outcomes Patient overall assessment of efﬁcacy: 5-point scale (responder = “excellent”) Reduction in pain at rest: VAS (mean) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “computer-generated randomisation sys- bias) tem”

Allocation concealment (selection bias) Unclear risk Not reported

Blinding (performance bias and detection Low risk “Placebo patch was identical in appearance, bias) colour and odour” All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described All outcomes

Study duration High risk 2 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Burgos 2001

Methods R, DD, AC, parallel groups Assessed at baseline, 7, 14 days

Participants Soft tissue rheumatism (tendinitis, bursitis, adhesive capsulitis), mean duration of symptoms 3 to 4 months

N = 129 M 31, F 87 Mean age 55 years Baseline pain ≥ 50 mm

Interventions (1) Flurbiprofen LAT, 2 x patch (= 40 mg) daily + placebo cream 3 x daily, n = 64 (2) Piketoprofen cream 1.8%, 3 x 4 cm (~ 36 mg) daily + placebo patch 2 x daily, n = 65 Cream applied 3 times daily, followed by patch after 15 minutes twice daily for 14 days Rescue medication: paracetamol 500 mg (maximum 4 g daily)

Outcomes Relief from treatment Pain at rest: VAS (mean) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “computer-generated randomisation list” bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk Double dummy technique bias) All outcomes

Incomplete outcome data (attrition bias) High risk Imputation: LOCF. “Other” attrition > All outcomes 10%

Study duration High risk 2 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Conaghan 2013

Methods Topical: R, DB, VC; oral: R, DB, PC Participants blinded to treatment or control, but not to topical or oral Assessed at baseline, 2, 6, 9, 12, weeks at clinic

Participants OA knee (function class I-III and ACR criteria) with ﬂare, PI (index knee) on walking ≥4/10 N = 1395 Mean age 61 years (range 24 to 90) M 475, F 920

Mean baseline PI 4.8/10

Interventions (1) Ketoprofen (IDEA-033) gel 2 x 50 mg daily, n = 233 (2) Ketoprofen (IDEA-033) gel 2 x 100 mg daily, n = 230 (3) Vehicle 2 x 2.2 g daily, n = 238 (4) Vehicle 2 x 4.4 g daily, n = 235 (5) Oral celecoxib 2 x 100 mg daily. N = 235 (6) Oral placebo, n = 228 (vehicle = TDT-064) Gel applied twice daily for 12 weeks to intact skin on sides and back of knee, avoiding patella and any wounds. Spread evenly with ﬁngers then left to dry ≥ 15 mins before covering Washout: ≥ 5 days or 5 x half life of analgesic Rescue medication: paracetamol up to 4 x 500 mg daily, but not within 24 h of any study visit. Participants needing ≥ 2 g daily or other analgesic for > 3 successive days were considered treatment failures

Outcomes Pain, function, stiffness: 11-point NRS WOMAC subscales Responder: ≥ 50% improvement in PI at week 12 (also for ≥ 30% and ≥ 80%) PGE: 5-point scale (responder = “good” or “excellent”) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5 Sponsor: IDEA AG, Germany

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “list generated by a random permuted bias) block scheme”

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk “matching gels”; “same primary packaging bias) for active and placebo treatments”; “dosing All outcomes aids virtually identical”

Incomplete outcome data (attrition bias) Low risk BOCF imputation for missing data and All outcomes lack of efﬁcacy

Study duration Low risk 12 weeks

Size Low risk > 200 participants per treatment group

Methods R, DD, AC parallel groups Assessed at baseline, 2, 4 weeks

Participants Knee osteoarthritis (“well documented, mild”) N = 235 M 80, F 155 Mean age 63 years Baseline pain moderate (median 3-4/9)

Interventions (1) Piroxicam gel 0.5%, 3 x 1 g (= 5 mg piroxicam) + placebo tablet daily, n = 117 (2) Ibuprofen tablet 3 x 400 mg + placebo cream daily, n = 118 Cream (3 cm ribbon) rubbed in to affected knee joint + 1 tablet taken orally 3 times daily for up to 4 weeks Washout: 7 days Rescue medication: paracetamol (maximum 4 g daily)

Outcomes PGE: 4-point scale (responder = “good” or “excellent”) Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1. Total = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk Double dummy technique bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described. “Other” attrition ~ 8% All outcomes

Study duration Unclear risk 4 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Methods R, DB, PC, parallel groups Assessed at baseline, 4, 7, 15 days

Participants Knee osteoarthritis, diagnosed radiographically, with at least moderate spontaneous pain N = 155 M 35, F 120 Mean age 67 years Baseline pain ≥ 57/100

Interventions (1) Diclofenac (DHEP) patch (= 180 mg), n = 78 (2) Placebo patch, n = 77 Patch applied twice daily (held by slightly elastic net) for 15 days Washout: 7 days if NSAIDs had been used Rescue medication: paracetamol 500 mg after 4 days

Outcomes PGE: 5-point scale (responder = “good” or “excellent”) Pain intensity: VAS (mean) Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1. Total = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk “matched placebo plaster” bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described All outcomes

Study duration High risk 2 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Methods R, DB, PC, parallel group Assessed at baseline, 30 days

Participants OA knee diagnosed using ACR criteria (no ﬂare required) N = 74 M 4, F 70 Mean age 54 years Mean baseline pain > 5/10

Interventions (1) Nimesulide gel 1% (Sulidin) 0.4 mg/10 cm2, n = 51 Placebo gel, n = 23 (2) Medication applied x 3 daily Gel rubbed in for < 1 minute, 3 times daily for 30 days Rescue medication: paracetamol (maximum 2 g daily), but not on day of evaluation

Outcomes PGE: 5-point scale (responder = “effective” and “very effective”) WOMAC scores for individual components and overall: mean data Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1. Total = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk “identical (color and odor) gel preparation bias) containing only vehicle” All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described. Total withdrawals low All outcomes

Study duration Unclear risk 4 weeks

Size High risk < 50 participants in placebo arm, 51 in active arm

Methods R, DB, PC, parallel groups Assessed at baseline, 3, 5, 7, 14 days

Participants Inﬂammatory peri- and extra-articular rheumatological diseases N = 60 M 10, F 50 Mean age 57 years Baseline pain on pressure severe

Interventions (1) Diclofenac (DHEP), 2 x plaster (= 180 mg) daily, n = 30 (2) Placebo, 2 x plaster daily, n = 30 Patch applied to affected area twice daily for 14 days Stable (> 2 months) systemic treatment continued unchanged, more recent treatment suspended. Rescue medication: paracetamol when strictly necessary

Outcomes No dichotomous data Pain on pressure: 4-point scale (mean) Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1. Total = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk “matched placebo plaster” bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described. No withdrawals reported All outcomes

Study duration High risk 2 weeks

Size High risk < 50 participants per treatment arm

Methods R, DB, PC, parallel groups Assessment at baseline, 7, 21 days

Participants Osteoarthritis of the knee (in ﬂare condition at baseline), diagnosed radiographically and by symptoms, of ≥ 3 months’ duration, requiring drug therapy N = 74 M 29, F 45 Mean age 62 years Mean baseline pain ≥ 40 (WOMAC pain subscale)

Interventions (1) Diclofenac with lecithin gel, 2%, 3 x 2.5 g daily, n = 38 (2) Placebo gel, n = 36 Level scoop of gel (2.5 g) applied to target knee, 3 times daily for 3 weeks, with rubbing for 2 to 20 seconds and no occlusion. Strenuous activity and bathing to be avoided ± 1 h Rescue medication: paracetamol. No other concomitant medication for OA allowed

Outcomes PGE: 4-point scale (responder = “none” or “mild”) PI: WOMAC pain subscale (mean) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB1, W1. Total = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “computer generated randomization bias) scheme”

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Unclear risk Not described bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described. Total withdrawals low All outcomes

Study duration High risk 3 weeks

Size High risk < 50 participants per treatment arm

Methods R, DB, PC, parallel groups Assessed at baseline and end of study

Participants Mixed conditions: osteoarthritis, periarthritis and degenerative diseases of the tendons N = 40 M 16, F 24 Mean age 48 years Mean baseline pain 2.2 (scale 0 to 3)

Interventions (1) Ibuprofen cream, n = 20 (strength, dose, quantity not reported) (2) Placebo cream, n = 20 Cream applied twice daily for 3 weeks

Outcomes Pain on movement: responder = “improved” Spontaneous pain: responder = “improved” Adverse events Withdrawals

Notes Oxford Quality Score: R, DB2, W1. Total = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk “identical preparations guaranteed blind- bias) ing” [translated] All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described. Total withdrawals low All outcomes

Study duration High risk 3 weeks

Size High risk < 50 participants per treatment arm

Hohmeister 1983

Methods R, DB, PC, parallel group Assessed at baseline, 7, 14, 21 days

Participants Cervical and lumbar back pain N = 100 M 55, F 43 Age 17 to 72 years

Baseline pain not reported

Interventions (1) Flufenamate 3% plus salicylate 2% gel (Mobilisin), n = 49 (quantity not reported) (2) Placebo gel, n = 51 Gel applied 3 times daily for 3 weeks

Outcomes Patient-rated improvement: (responder = “substantial” or “moderate”) Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1. Total = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Unclear risk Tubes indistinguishable bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described. No withdrawals reported All outcomes

Study duration High risk 3 weeks

Size High risk < 50 participants in active treatment arm, 51 in placebo arm

Kneer 2013

Methods R, DB, VC, parallel group Assessed at baseline, 2, 6, 12 weeks at clinic, and daily diary for ﬁrst 2 weeks

Participants OA knee > 6 months (function class I-III and ACR criteria) with ﬂare N = 866 (ITT 828) Mean age 62 years (range 19 to 78) M 235, F 593 Mean baseline pain 65/100

Interventions (1) Ketoprofen (IDEA-033) gel 2 x 25 mg daily, n = 223 (2) Ketoprofen (IDEA-033) gel 2 x 50 mg daily, n = 223 (3) Ketoprofen (IDEA-033) gel 2 x 100 mg daily, n = 221 (4) Vehicle, n = 199

Gel applied twice daily for 12 weeks to intact skin on sides and back of knee, avoiding patella. Spread evenly with ﬁngers then left to dry ≥ 15 mins before covering. Speciﬁcally no rubbing, kneading, massaging Washout: 5 x half life of analgesic + 2 days Rescue medication: paracetamol up to 2 g daily for ≥ 5 days in any 7-day period, but not within 48 h of any study visit

Outcomes Pain, function, stiffness: 11-point NRS WOMAC subscales OMERACT-OARSI responder at ﬁnal visit PGE: 5-point scale (responder = “good” or “excellent”) Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1. Total = 4 Sponsor: IDEA AG, Germany

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Method of sequence generation not de- bias) scribed

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk “matching amount”; “identical in terms of bias) appearance and constituents (with the ex- All outcomes ception of ketoprofen)”

Incomplete outcome data (attrition bias) Unclear risk Imputation not mentioned All outcomes

Study duration Low risk 12 weeks

Size Unclear risk 50 to 200 participants per treatment group as analysed

Link 1996

Methods R, DB, PC, parallel group Assessed at baseline 3, 7, 14, days

Participants Non-articular rheumatism N = 115 M/F not reported Age not reported Baseline pain not reported

Interventions (1) Ketoprofen gel 2.5%, n = 56 (2) Placebo gel, n = 59 Gel applied as 4 to 10 cm strip 3 to 4 times daily for 2 weeks No antirheumatic medication during trial

Outcomes No patient-rated outcomes Withdrawals

Notes Oxford Quality Score: R2, DB1, W0. Total = 3

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “zufallsgenerator” [random numbers gen- bias) erator]

Allocation concealment (selection bias) Low risk Randomisation number corresponded to number on medication

Blinding (performance bias and detection Unclear risk Not described bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described All outcomes

Study duration High risk 2 weeks

Size Unclear risk 50 to 200 participants per treatment arm

McCleane 2000

Methods R, DB, PC, and AC, parallel group Assessed at baseline, 1, 2, 3, 4 weeks

Participants Localised musculoskeletal pain ≥ 3 months N = 100 M/F inconsistent data Mean age 46 years Mean pain score in week before treatment: 62.3/100 mm

Interventions (1) Piroxicam gel 2.5%, n = 50 (2) Glyceryl trinitrate 1%, n = 50 (3) Piroxicam 2.5% + glyceryl trinitrate 1% gel, n = 50 (4) Placebo gel, n = 50 Gel applied as “small volume” to painful area 3 times daily for 4 weeks

Outcomes PR: responder = 50% PR PI: VAS (mean) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “computer-generated random number list” bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk Creams were “all off-white/yellow in colour bias) and put in identical brown glass containers” All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described. “Other” withdrawals > 10% All outcomes

Study duration Unclear risk 4 weeks

Size High risk 50 participants per treatment arm, not all contributed data

NCT01980940

Methods Randomised, double-blind, cross-over study Assessed at 2, 4, 7, 11, 14 days

Participants OA knee for > 6 months (clinical and radiological criteria), ARA functional Class I, II, or III, age 40 years or older N = 70 Men and women

Interventions (1) Etoricoxib 50 mg (1.31 mL, 4% DMSO gel) (2) Placebo gel (Unclear if placebo gel contained DMSO) Gel applied twice daily to the affected knee

Outcomes Change in pain (group mean) over 14 days PGE: 5-point scale (responder = “well” and “very well”) at 14 days Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1. Total = 4 Completed November 2014

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Method of sequence generation not de- bias) scribed

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk “matching placebo” bias) All outcomes

Incomplete outcome data (attrition bias) Low risk Imputation not mentioned, but no with- All outcomes drawals

Study duration Unclear risk 2 weeks

Size High risk < 50 participants per treatment arm (24)

Niethard 2005

Methods R, DB, PC, parallel groups Assessed weekly at study centre and daily with patient diaries

Participants OA knee, clinically diagnosed, symptomatic, with pain > 50/100 mm and > “moderate” on 4-point scale N = 238 M 87, F 151 Mean age 66 years Mean baseline pain 67/100 mm

Interventions (1) Diclofenac 1.16% gel (Voltaren Emulgel), n = 117 (2) Placebo gel, n = 121 Gel (4 g) applied to front of knee and rubbed in for ≥ 1 minute 4 times daily for 3 weeks Rescue medication: paracetamol (maximum 2 g daily)

Outcomes PGE: 5-point scale (responder = “very good” and “excellent”) OMERACT-OARSI responder at end of trial Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “computer-generated” bias)

Allocation concealment (selection bias) Low risk Remote allocation. Each site assigned a series of numbers and kits. Patients assigned lowest number available

Blinding (performance bias and detection Low risk Gels were “identical in colour, feel, and ap- bias) pearance” All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described. “Other” withdrawals > 10% All outcomes

Study duration High risk 3 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Ottillinger 2001

Methods R, DB, PC, parallel group Assessment at baseline, 1, 2, 3, 4 weeks

Participants Knee osteoarthritis, diagnosis according to ACR criteria, symptomatic. Age > 50 years N = 234 M 53, F 181 Mean age 67 years Baseline pain > 50 mm

Interventions (1) Eltenac gel 0.1%, n = 57 (2) Eltenac gel 0.3%, n = 59 (3) Eltenac gel 1.0%, n = 59 (4) Placebo gel, 3 x 3 g daily, n = 59 Gel applied to affected knee joint, with rubbing, as 4 inch string (approximately 3 g gel) 3 times daily for 4 weeks; to give 9 mg, 27 mg, 90 mg daily doses Washout: 7 days Rescue medication: paracetamol (maximum 2 g daily) if strictly necessary

Outcomes PGE: verbal rating scale (no details) PI: 10 cm VAS (mean) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “random plan”, generated a priori using bias) method of permuted blocks

Allocation concealment (selection bias) Low risk Remote randomisation. Labelling included no identiﬁcation of the actual treatment group

Blinding (performance bias and detection Low risk Active and placebo gels were “indistin- bias) guishable in appearance, handling and la- All outcomes belling”

Incomplete outcome data (attrition bias) Unclear risk N/A - no useable efﬁcacy data. “Other” All outcomes withdrawals > 10%

Study duration Unclear risk 4 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Poul 1993

Methods R, DB, PC, parallel groups Assessed at baseline, 7, 14 days

Participants Local, non-articular form of rheumatism, with moderate to severe pain, requiring treatment N = 104 M 55, F 49 Mean age 47 years Baseline pain moderate or severe

Interventions (1) Flurbiprofen patch, n = 53 (2) Placebo patch, n = 51 Patch (= 40 mg ﬂurbiprofen) applied to affected area twice daily for 14 days. Bathing allowed only at times of patch changes Rescue medication: paracetamol (maximum 4 g daily). Other analgesia and physiotherapy not allowed

Outcomes No dichotomous efﬁcacy data Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1. Total = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk Placebo patch “non-medicated, but other- bias) wise identical” All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described. “Other” withdrawals < 10% All outcomes

Study duration High risk 2 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Rose 1991

Methods R, DB, PC, parallel group Assessed at baseline, 3, 7, 10, 14 days

Participants Gonarthrosis, symptomatic N = 30 M/F not reported Age 42 to 83 years Baseline pain not reported (but all inpatients)

Interventions (1) Piroxicam gel 5%, n = 15 (2) Placebo gel, n = 15 Gel (1 mg = 5 mg piroxicam) applied 4 times daily for up to 14 days

Outcomes PGE: 4-point scale (responder = “good” or “excellent”) PI: VAS (mean data) Adverse events

Notes Oxford Quality Score: R1, D1, W0. Total = 2

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Unclear risk Not described bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described All outcomes

Study duration High risk 2 weeks

Size High risk < 50 participants per treatment arm

Roth 1995

Methods R, DB, PC, parallel group Assessed at baseline, 7, 14 days

Participants Osteoarthritis requiring NSAID treatment ≥ 1 month N = 119 M 16, F 103 Mean age 67 years Baseline pain 3.3 (scale 1 to 5)

Interventions (1) Diclofenac 3% + hyaluron 2.5% gel, n = 59 (2) Placebo + hyaluron 2.5% gel, n = 60 Gel (2 g) applied 4 times daily for 2 weeks Stable doses of NSAID continued unchanged. No other analgesics allowed

Outcomes No dichotomous data PI: 5-point scale (mean change) Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1. Total = 4

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk “identical placebo gel” bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not described. Total withdrawals low All outcomes

Study duration High risk 2 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Roth 2004

Methods R, DD, PC, and AC, parallel group Assessed at baseline, 2, 4, 6 weeks at clinic and daily patient diaries

Participants OA knee with ﬂare, and duration ≥ 6 months N = 397 M 160, F 237 Mean age 63 years Mean baseline pain > 66/100

Interventions (1) Ketoprofen gel (IDEA-33) 2 x 110 mg daily, n = 138 (2) Celecoxib tabs 2 x 100 mg daily, n = 132 (3) Placebo gel and tabs, n = 127 Gel (measured) applied to knee twice daily for 6 weeks Rescue med: paracetamol

Outcomes PGE: 5-point scale (responder = “good” or “excellent”) OMERACT-OARSI responder at ﬁnal visit Pain on movement: 100 mm VAS (mean data) WOMAC subscales: pain, stiffness, and physical function (mean data) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “computer-generated randomization bias) schedule by outside consultant”

Allocation concealment (selection bias) Low risk Remote allocation. Each site assigned a series of numbers and kits. Participants assigned sequentially

Blinding (performance bias and detection Low risk “The two study solutions were identical bias) clear, colourless liquids in opaque bottles All outcomes with labels identical except for patient iden-

tiﬁcation number”

Incomplete outcome data (attrition bias) Low risk Imputation using BOCF where necessary. All outcomes “Other” withdrawals < 10%

Study duration Low risk 6 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Rother 2007

Methods R, DB, PC, parallel group Assessed at baseline, 1, 6, and 12 weeks

Participants Primary OA in at least 1 knee, defined by radiological findings and flare of pain after washout of stable therapy N = 326 M 105, F 221 Mean age 64 years Mean baseline pain 13/20

Interventions (1) Diclofenac 1.5% in DMSO (45.5%), n = 164 (2) Vehicle with DMSO, n = 162 Medication (40 drops) applied 4 times daily for 12 weeks Rescue medication: paracetamol, maximum 3 g daily, not during washout period and 3 days before ﬁnal assessment at week 12

Outcomes ≥ 50% PR (provided by author) Change from baseline to ﬁnal assessment in pain and physical function (WOMAC score) Global clinical assessment (5-point Likert scale) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “Study kits were prepared and numbered bias) according to a computer-generated randomisation schedule”

Allocation concealment (selection bias) Low risk “The randomisation schedule was concealed from the investigators and their support staff, study patients, and the sponsor’s clinical research personnel until ﬁnal data lock and transfer to the statistician”

Incomplete outcome data (attrition bias) Low risk Imputation: All outcomes primary outcome using BOCF imputation supplied by author. “Other” withdrawals < 10%

Study duration Low risk 12 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Rother 2013

Methods R, DB, VC, parallel group Assessment at baseline, 2, 6, 9, 12 weeks at clinic and daily diary for ﬁrst 14 days

Participants OA knee (function class I-III and ACR criteria), PI (index knee) on walking ≥ 4/10. No ﬂare required for inclusion N = 555 Mean age 62 years (SD 11) M 209, F 346 Mean baseline pain 5.2 (SD 1.0)

Interventions (1) Ketoprofen (IDEA-033) gel 2 x 100 mg daily, n = 274 (2) Vehicle 2 x 4.4 g daily, n = 281 Gel applied to knee twice daily for 12 weeks Washout: ≥ 5 days Rescue medication: paracetamol up to 4 x 500 mg daily, but not within 24 h of any study visit. Participants needing ≥ 2 g daily or other analgesic for > 3 successive days were considered treatment failures

Outcomes Pain, function, stiffness: 11-point NRS WOMAC subscales Responder: ≥ 50% improvement in PI at week 12 PGE: 5-point scale (responder = “good” or “excellent”) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB1, W1. Total = 4 Sponsor: IDEA AG, Germany

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “list generated by a random permuted bias) block scheme”

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Unclear risk Not described bias) (Likely to be adequate) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Imputation for dichotomous outcomes not All outcomes reported

Study duration Low risk 12 weeks

Size Low risk > 200 participants per treatment group

Sandelin 1997

Methods R, DD, PC, and AC, parallel group

Participants Osteoarthritis of the knee, radiologically conﬁrmed, pain symptoms for most days in last month, requiring treatment. Patients with severe OA or pain excluded N = 290 M 101, F 189 Mean age 61 years Baseline pain ≥ 48/100

Interventions (1) Eltenac 1% gel + placebo tablets, n = 126 (2) Diclofenac 50 mg tablets + placebo gel, n = 82 (3) Placebo gel and tablets, n = 82 Tablets (50 mg or placebo) taken morning and evening with food, and gel (3 g = 30 mg eltenac or placebo, measured with spoon) applied 3 times daily, with gentle rubbing, for 4 weeks. In bilateral cases, both knees were treated with the same regimen Rescue medication: not reported. No new physical therapies allowed, but physiotherapy or orthotic devices started ≥ 7 days before study to be continued

Outcomes PGE: 4-point scale - only physician evaluation reported Overall pain in preceding week (10 cm VAS) - mean data reported Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB 2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “random plan generated using PROC PLAN SAS bias) version 6.07”

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk Double dummy technique bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk N/A - no useable efﬁcacy data. Total withdrawals All outcomes < 10%

Study duration Unclear risk 4 weeks

Size Unclear risk 50 to 200 participants per treatment group

Simon 2009

Methods R, DB (DD), PC, VC, and AC study Assessments at baseline, 4, 8, and 12 weeks or at dropout

Participants Primary OA, conﬁrmed radiographically, with pain requiring regular analgesic, and ﬂare following washout N = 755 M 490, F 292 Mean age 64 years Mean baseline pain 288/500

Interventions (1) Diclofenac solution 1.5% (with DMSO 45.5%, Pennsaid®) + oral placebo, n = 154 (2) DMSO (45.5%) vehicle solution + oral placebo, n = 155 (3) Placebo solution (with 2.3% DMSO) + oral placebo, n = 161 (4) Placebo solution (with 2.3% DMSO) + 100 mg slow-release oral diclofenac, n = 151 Treatment with 40 drops solution, 4 times a day around entire circumference of the knee, plus 1 capsule daily, taken orally, for 12 weeks Rescue medication: paracetamol (maximum 1300 mg daily) permitted except during 3 days before each efﬁcacy assessment

Outcomes ≥ 50% PR (provided by authors) WOMAC pain and physical function measured on 5-point Likert scale Patient overall health assessment WOMAC stiffness Patient global assessment of knee OA Adverse effects Withdrawals

Notes Oxford Quality Score: R2, DB 2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “Each study kit was assembled accord- bias) ing to a computer-generated randomisation schedule created by an external statistician”

Allocation concealment (selection bias) Low risk “The randomisation sequence was concealed from investigators, subjects and the sponsor’s clinical research personnel until after data lock”

Blinding (performance bias and detection Low risk “All study solutions were identical clear, bias) colourless liquids” “it was expected that All outcomes some subjects applying topical diclofenac or DMSO vehicle solution would report a garlic taste or odour from exhaling dimethyl sulphide... [therefore] a token amount of DMSO (2.3%) was included in the placebo solution”

Incomplete outcome data (attrition bias) Low risk Imputation: All outcomes primary outcome using BOCF imputation supplied by author. “Other” withdrawals ≥ 10%, equally distributed between groups

Study duration Low risk 12 weeks

Size Unclear risk 50 to 200 participants per treatment group

Tugwell 2004

Methods R, DD, AC, parallel group Assessed at baseline, 12 weeks, or at dropout

Participants OA knee, symptomatic, radiologically conﬁrmed (no ﬂare required) N = 622 (604 analysed) M 266, F 356 Mean age 64 years Mean baseline pain 288/500

Interventions (1) Diclofenac solution 1.5% (with DMSO 45.5%, Pennsaid®) + placebo capsule, n = 311 (2) Diclofenac capsule + placebo solution, n = 311 Medication applied as 50 drops of solution applied around affected knee (front, back, and sides) without massage, plus oral capsule (50 mg diclofenac or placebo), 3 times daily for 12 weeks (daily total 4.6 mL = 75 mg diclofenac or placebo)

Outcomes OMERACT-OARSI responder Patient global assessment on a 100 mm VAS - mean data reported Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “computer generated” bias)

Allocation concealment (selection bias) Low risk Sequence generated by external statistician and concealed until ﬁnal data lock and transfer of data to external statistician

Blinding (performance bias and detection Low risk Active and placebo solutions were both bias) clear and colourless and in identical bottles. All outcomes Placebo solution included small amount of DMSO to give characteristic odour on application. Capsules for diclofenac and placebo were identical

Incomplete outcome data (attrition bias) Unclear risk Not described. “Other” withdrawals > All outcomes 10%, distributed between groups

Study duration Low risk 12 weeks

Size Low risk > 200 participants per treatment group van Haselen 2000

Methods R, DB, AC, parallel group Assessed at baseline, 28 days

Participants Osteoarthritis of the knee, radiographically conﬁrmed N = 184 M 48, F 136 Mean age 64 years Mean baseline pain on walking ≥ 50 mm

Interventions (1) Piroxicam gel 0.5% (Feldene), n = 92 (2) Homeopathic gel (SRL*), n = 92 Gel (1 g, measured with spatula) applied to worst affected knee 3 times daily for 4 weeks Rescue medication: paracetamol (maximum 3 g daily). Stable oral NSAIDs and other medication continued during trial

* SRL contains comfrey, poison ivy and marsh tea

Outcomes PGE: 6-point scale (responder = “good” or “excellent”) PI: 100 mm VAS (mean) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated bias)

Allocation concealment (selection bias) Low risk Third party allocation, sealed boxes

Blinding (performance bias and detection Low risk Tubes made to look identical and patients bias) did not open medication boxes until they All outcomes returned home. In 5 cases masking of tube identity was compromised

Incomplete outcome data (attrition bias) Low risk Imputation: missing values assume the All outcomes worst possible outcome. Total withdrawals < 10%

Study duration Unclear risk 4 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Varadi 2013

Methods R, DB, PC, parallel group Assessment at baseline, 1 and 2 weeks

Participants Primary OA knee in single joint (grade II or III), radiologically conﬁrmed and symp- tomatically active, PI at rest ≥ 40/100. Treatment naive and requiring treatment or dis- satisﬁed with treatment N = 75 Mean age 61 years (SD 11) M 27, F 48

Interventions (1) VALE-ibuprofen cream 2 x 2 g daily, n = 39 (2) Placebo cream, n = 36 Medication applied twice daily for 2 weeks using ribbon method and dosing card (2 g dose) Rescue medication: paracetamol up to 4 x 500 mg daily, but not within 24 h of any

study visit. No more than 2 g daily for 3 successive days

Outcomes Pain, function, stiffness: 11-point NRS WOMAC subscales PGE: 7-point scale (mean data reported) Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W0. Total = 4 Sponsor: BioChemics, Inc

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “A randomization list (in blocks of 4 sub- bias) jects) was produced by the Biometric De- partment of PFC”

Allocation concealment (selection bias) Low risk Remote allocation, packed and labelled for each patient

Blinding (performance bias and detection Low risk “Investigators were randomly provided bias) with blinded samples of either ibuprofen or All outcomes placebo in 100 g tubes”

Incomplete outcome data (attrition bias) Unclear risk Imputation not mentioned All outcomes

Study duration High risk 2 weeks

Size High risk < 50 participants per treatment arm

Widrig 2007

Methods R, DB, AC, parallel group Assessment at baseline and 21 days

Participants OA of hand (ACR criteria). Pain intensity of at least 40/100 mm (VAS) N = 198 M 51, F 147 Mean age 64 years Mean baseline pain 67 mm

Interventions (1) Ibuprofen gel 5% (Optifen), n = 98 (2) Arnica gel 50%, n = 100 Medication applied as 4 cm strip of gel gently rubbed into affected joints 3 times daily for 3 weeks Rescue medication: paracetamol 500 mg, except 24 h before ﬁnal evaluation

Outcomes PGE: 4-point scale Reduction in pain, measured by 100 mm VAS Functional capacity of the hand using HAI assessment Adverse events Withdrawals

Notes Oxford Quality Score: R2, DB2, W1. Total = 5

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk “Randomisation codes were computer- bias) generated in blocks of four”

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk “Double-blindness was assured by identi- bias) cal packing, as well as gel appearance and All outcomes consistency” “there was a slight difference in odour for the ﬁrst 30 seconds after application, after which both were odourless”

Incomplete outcome data (attrition bias) Unclear risk Not described. “Other” withdrawals ± All outcomes 10%, distributed between groups

Study duration High risk 3 weeks

Size Unclear risk 50 to 200 participants per treatment arm

Zacher 2001

Methods R, DD, AC, PC Assessed at baseline, 3, 7, 14, 21 days

Participants Osteoarthritis of the ﬁnger joints, “activated” N = 321 M 38, F 283 Mean age 62 years (35 to 95 years) Baseline pain ≥ 40 mm

Interventions (1) Diclofenac Emulgel + placebo tablets, n = 165 (2) Ibuprofen tablets + placebo gel, n = 156 Gel (10 cm diclofenac diethylammonium 1.16% or placebo) applied 4 times daily, with massage, plus 2 tablets (400 mg ibuprofen or placebo) taken 3 times daily, for 3 weeks Rescue medication: paracetamol

Outcomes PI: 100 mm VAS for ’general pain’, ’pain at rest’ (responder = ≥ 40% reduction in general pain) Disease activity: 100 mm VAS Adverse events Withdrawals

Notes Oxford Quality Score: R1, DB2, W1

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described bias)

Allocation concealment (selection bias) Unclear risk Not described

Blinding (performance bias and detection Low risk Double dummy technique bias) All outcomes

Incomplete outcome data (attrition bias) Unclear risk Not true ITT analysis, but missing data All outcomes evenly distributed between groups. Use of unauthorised medication = non-responder

Study duration High risk 3 weeks

Size Unclear risk 50 to 200 participants per treatment arm

AC: active controlled; ACR: American College of Rheumatology; ARA: American Rheumatology Association; AUSCAN: Australian/ Canadian Osteoarthritis Hand Index; BOCF: baseline observation carried forward; DB: double blind; DD: double dummy; DHEP: diclofenac hydroxyethylpyrrolidine; DMSO: dimethyl sulphoxide; F: female; HAI: Hand Algofunctional Index; ITT: intention- to-treat; M: male; N: number of participants in study; n: number of participants in the treatment arm; N/A: not applicable; NRS: numerical rating scale; NSAID: nonsteroidal anti-inﬂammatory drug; OA: osteoarthritis; OARSI: Osteoarthritis Research Society International; OMERACT: Outcome Measures in Rheumatology Clinical Trials; PC: placebo-controlled; PGE: patient global evaluation; PI: pain intensity; PR: pain relief; R: randomised; VAS: visual analogue scale; VC: vehicle-controlled; WOMAC: Western Ontario and McMaster Universities Arthritis Index

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 68 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Allegrini 2009 8-day study (too short)

Di Rienzo Businco 2004 Not double-blinded

Doi 2010 Open-labelled study

Fotiades 1976 Duration of symptoms unclear; treatment duration 6 to 20 days only

Galer 2010 Healthy volunteers; no baseline pain

Geller 1980 No appropriate control (etofenamate versus diethylamine salicylate)

Ginsberg 1991 Duration of symptoms up to 30 days only (too short)

Mattara 1994 Mean duration of condition 26 days (too short)

Peniston 2011 Open-label extension of NCT00171691

Rovensky 2001 Trial duration only 8 days

Tiso 2010 Open-labelled study; only 9 participants in the placebo group

Trnavský 2004 Trial duration only 8 days

Underwood 2008 Open-labelled study

Verkleij 2015 Open-labelled study

Vitali 1980 Mixed acute and chronic conditions, including surgery

Characteristics of studies awaiting assessment [ordered by study ID]

Bohlooli 2012

Methods Randomised, double-blind, controlled study. Duration 4 weeks

Participants Primary OA knee with ﬂare after withdrawal of previous therapy N = 60 Age 40 to 85 years

Interventions Olive oil Piroxicam gel

Outcomes WOMAC and PGs standard questionnaires

Notes Completed Request for full paper sent to lead author 24 February 2015 Interventions repackaged in 60 g anonymous tubes - unclear if this is effective blinding for participants

Niempoog 2012

Methods Randomised, double-blind, controlled study. Duration 6 weeks

Participants OA knee N = 100

Interventions Plygersic gel (4% ginger and plai extract) Diclofenac 1% solution

Outcomes Knee Injury and Osteoarthritis Outcome Score

Notes Completed Request for full paper sent to lead author 24 February 2015 Abstract reports: Plygersic gel relieves joint pain and improves problematic symptoms and improves the quality of life in osteoarthritis knees during a 6-week treatment regimen with no differences to the 1% diclofenac gel group

OA: osteoarthritis; WOMAC: Western Ontario and McMaster Universities Arthritis Index

Characteristics of ongoing studies [ordered by study ID]

NCT01377038

Trial name or title Central pain mechanisms in osteoarthritis: a randomized, double-blind, crossover study to evaluate the effectiveness of topical diclofenac versus duloxetine for chronic osteoarthritis pain

Methods Randomised, double-blind, cross-over study. Duration ?8 weeks

Participants OA knee (ACR criteria), age 50 years or older N = 70 Men and women

Interventions Topical diclofenac, 4 times daily Oral duloxetine 20 to 30 mg daily

Outcomes Pain

Starting date September 2011

Contact information PI: Kristine Phillips, MD, PhD, University of Michigan

Notes Estimated primary completion: November 2015

NCT02068859

Trial name or title Treatment of knee pain with topical diclofenac cream 8% or diclofenac gel 1%

Methods Randomised, double-blind, parallel-group study. Duration 6 weeks

Participants Acute and chronic knee pain, along with postoperative knee pain lasting at least two months, age 18 years and older Estimated N = 106 Men and women

Interventions Diclofenac cream 8% applied 3 - 4 times daily for 6 weeks Diclofenac gel 1% applied 3 - 4 times daily for 6 weeks

Outcomes Pain scores

Starting date January 2014

Contact information FPR Specialty Pharmacy

Notes Estimated completion date January 2015

NCT02121002

Trial name or title

Methods Randomised, double-blind, parallel-group study. Duration 4 weeks

Participants OA knee, clinical diagnosis and Kellgren-Lawrence grade 1 - 3 disease, ≥ moderate pain on movement after discontinuing pain medication for ≥ 7 days, age 35 years or older N = 1176 Men and women

Interventions Diclofenac Sodium Topical Gel, 1%. 4 g, 4 times a day for 4 weeks Voltaren Topical Gel, 1%. 4 g, 4 times a day for 4 weeks Vehicle Diclofenac Sodium Topical Gel. 4 g, 4 times a day for 4 weeks (placebo)

Outcomes Pain score and change in pain (group mean) over 4 weeks

Starting date

Contact information

Notes Completed October 2014

ACR: American College of Rheumatology; N: number of participants in study; OA: osteoarthritis

Comparison 1. Topical diclofenac versus carrier

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Clinical success 9 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only 1.1 Duration 6 to 12 weeks 4 2343 Risk Ratio (M-H, Fixed, 95% CI) 1.20 [1.12, 1.29] 1.2 2 to ≤ 6 weeks 5 732 Risk Ratio (M-H, Fixed, 95% CI) 1.86 [1.50, 2.31] 2 Local adverse events 13 3658 Risk Ratio (M-H, Fixed, 95% CI) 1.84 [1.54, 2.21] 3 Systemic adverse events 7 1266 Risk Ratio (M-H, Fixed, 95% CI) 0.89 [0.59, 1.34] 4 Gastrointestinal adverse events 10 3240 Risk Ratio (M-H, Fixed, 95% CI) 1.10 [0.76, 1.58] 5 Withdrawals due to adverse 12 3552 Risk Ratio (M-H, Fixed, 95% CI) 1.55 [1.14, 2.11] events 6 Withdrawals due to lack of 11 3455 Risk Ratio (M-H, Fixed, 95% CI) 0.59 [0.47, 0.75] efﬁcacy

Comparison 2. Topical ketoprofen versus carrier

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Clinical success 4 Odds Ratio (M-H, Fixed, 95% CI) Subtotals only 1.1 Duration 6 to 12 weeks 4 2573 Odds Ratio (M-H, Fixed, 95% CI) 1.22 [1.03, 1.45] 2 Local adverse events 4 2621 Risk Ratio (M-H, Fixed, 95% CI) 1.04 [0.85, 1.27] 3 Gastrointestinal adverse events 4 2621 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.69, 1.32] 4 Withdrawals due to adverse 4 2621 Risk Ratio (M-H, Fixed, 95% CI) 1.28 [0.92, 1.78] events 5 Withdrawals due to lack of 4 2885 Risk Ratio (M-H, Fixed, 95% CI) 1.11 [0.80, 1.55] efﬁcacy

Comparison 3. Topical NSAID versus oral NSAID

No. of No. of Outcome or subgroup title studies participants Statistical method Effect size

1 Clinical success 5 1735 Risk Ratio (M-H, Fixed, 95% CI) 1.03 [0.95, 1.12] 2 Local adverse events 5 1651 Risk Ratio (M-H, Fixed, 95% CI) 3.74 [2.76, 5.06] 3 Gastrointestinal adverse events 6 1961 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.56, 0.77] 4 Withdrawals due to adverse 6 1961 Risk Ratio (M-H, Fixed, 95% CI) 0.85 [0.68, 1.06] events 5 Withdrawals due to lack of 3 1197 Risk Ratio (M-H, Fixed, 95% CI) 2.47 [1.45, 4.22] efﬁcacy

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 73 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.1. Comparison 1 Topical diclofenac versus carrier, Outcome 1 Clinical success.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 1 Topical diclofenac versus carrier

Outcome: 1 Clinical success

Studyorsubgroup Diclofenac Carrier RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Duration 6 to 12 weeks Altman 2009 130/198 106/187 18.5 % 1.16 [ 0.99, 1.36 ]

Baer 2005 46/105 27/107 4.5 % 1.74 [ 1.17, 2.57 ]

Baraf 2011 461/719 394/705 67.5 % 1.15 [ 1.05, 1.25 ]

Roth 2004 79/163 55/159 9.4 % 1.40 [ 1.07, 1.83 ] Subtotal (95% CI) 1185 1158 100.0 % 1.20 [ 1.12, 1.29 ] Total events: 716 (Diclofenac), 582 (Carrier) Heterogeneity: Chi2 = 5.97, df = 3 (P = 0.11); I2 =50% Test for overall effect: Z = 4.94 (P < 0.00001) 22to ≤ 6 weeks Bookman 2004 44/84 26/79 31.6 % 1.59 [ 1.09, 2.32 ]

Bruhlmann 2003 12/51 4/52 4.7 % 3.06 [ 1.06, 8.86 ]

Dreiser 1993 55/78 21/77 24.9 % 2.59 [ 1.75, 3.83 ]

Grace 1999 12/38 9/36 10.9 % 1.26 [ 0.61, 2.63 ]

Niethard 2005 36/117 24/120 27.9 % 1.54 [ 0.98, 2.41 ] Subtotal (95% CI) 368 364 100.0 % 1.86 [ 1.50, 2.31 ] Total events: 159 (Diclofenac), 84 (Carrier) Heterogeneity: Chi2 = 5.97, df = 4 (P = 0.20); I2 =33% Test for overall effect: Z = 5.61 (P < 0.00001) Test for subgroup differences: Chi2 = 14.09, df = 1 (P = 0.00), I2 =93%

0.5 0.7 1 1.5 2 Favours carrier Favours diclofenac

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 74 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.2. Comparison 1 Topical diclofenac versus carrier, Outcome 2 Local adverse events.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 1 Topical diclofenac versus carrier

Outcome: 2 Local adverse events

Studyorsubgroup Diclofenac Carrier RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI 102-93-1 21/41 6/42 4.2 % 3.59 [ 1.61, 7.97 ]

Altman 2009 9/198 4/187 2.9 % 2.13 [ 0.67, 6.78 ]

Baer 2005 42/107 23/109 16.1 % 1.86 [ 1.21, 2.87 ]

Baraf 2011 34/721 4/704 2.9 % 8.30 [ 2.96, 23.27 ]

Bookman 2004 30/84 11/80 8.0 % 2.60 [ 1.40, 4.82 ]

Bruhlmann 2003 3/51 2/52 1.4 % 1.53 [ 0.27, 8.77 ]

Dreiser 1993 1/78 2/77 1.4 % 0.49 [ 0.05, 5.33 ]

Galeazzi 1993 0/30 0/30 Not estimable

Grace 1999 4/38 7/36 5.1 % 0.54 [ 0.17, 1.69 ]

Niethard 2005 4/117 3/120 2.1 % 1.37 [ 0.31, 5.98 ]

Roth 1995 12/59 26/60 18.3 % 0.47 [ 0.26, 0.84 ]

Roth 2004 60/164 41/162 29.2 % 1.45 [ 1.04, 2.02 ]

Simon 2009 41/154 12/157 8.4 % 3.48 [ 1.90, 6.37 ] Total (95% CI) 1842 1816 100.0 % 1.84 [ 1.54, 2.21 ] Total events: 261 (Diclofenac), 141 (Carrier) Heterogeneity: Chi2 = 45.44, df = 11 (P<0.00001); I2 =76% Test for overall effect: Z = 6.56 (P < 0.00001) Test for subgroup differences: Not applicable

0.05 0.2 1 5 20 Favours diclofenac Favours carrier

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 75 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.3. Comparison 1 Topical diclofenac versus carrier, Outcome 3 Systemic adverse events.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 1 Topical diclofenac versus carrier

Outcome: 3 Systemic adverse events

Studyorsubgroup Diclofenac Carrier RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Bruhlmann 2003 1/51 1/52 2.2 % 1.02 [ 0.07, 15.87 ]

Dreiser 1993 0/78 2/77 5.7 % 0.20 [ 0.01, 4.05 ]

Galeazzi 1993 0/30 0/30 Not estimable

Grace 1999 2/38 2/36 4.6 % 0.95 [ 0.14, 6.37 ]

Niethard 2005 7/117 8/120 17.8 % 0.90 [ 0.34, 2.40 ]

Roth 2004 19/164 16/162 36.2 % 1.17 [ 0.63, 2.20 ]

Simon 2009 10/154 15/157 33.4 % 0.68 [ 0.32, 1.47 ] Total (95% CI) 632 634 100.0 % 0.89 [ 0.59, 1.34 ] Total events: 39 (Diclofenac), 44 (Carrier) Heterogeneity: Chi2 = 2.18, df = 5 (P = 0.82); I2 =0.0% Test for overall effect: Z = 0.56 (P = 0.58) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours diclofenac Favours carrier

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 76 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.4. Comparison 1 Topical diclofenac versus carrier, Outcome 4 Gastrointestinal adverse events.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 1 Topical diclofenac versus carrier

Outcome: 4 Gastrointestinal adverse events

Studyorsubgroup Diclofenac Carrier RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Altman 2009 15/198 7/187 13.9 % 2.02 [ 0.84, 4.85 ]

Baraf 2011 3/721 3/704 5.9 % 0.98 [ 0.20, 4.82 ]

Bookman 2004 6/84 4/80 7.9 % 1.43 [ 0.42, 4.88 ]

Bruhlmann 2003 1/51 0/52 1.0 % 3.06 [ 0.13, 73.36 ]

Dreiser 1993 0/78 2/77 4.9 % 0.20 [ 0.01, 4.05 ]

Galeazzi 1993 0/30 0/30 Not estimable

Grace 1999 2/38 2/36 4.0 % 0.95 [ 0.14, 6.37 ]

Niethard 2005 0/117 2/120 4.8 % 0.21 [ 0.01, 4.23 ]

Roth 2004 19/164 15/162 29.1 % 1.25 [ 0.66, 2.38 ]

Simon 2009 10/154 15/157 28.7 % 0.68 [ 0.32, 1.47 ] Total (95% CI) 1635 1605 100.0 % 1.10 [ 0.76, 1.58 ] Total events: 56 (Diclofenac), 50 (Carrier) Heterogeneity: Chi2 = 6.57, df = 8 (P = 0.58); I2 =0.0% Test for overall effect: Z = 0.50 (P = 0.62) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours diclofenac Favours carrier

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 77 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.5. Comparison 1 Topical diclofenac versus carrier, Outcome 5 Withdrawals due to adverse events.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 1 Topical diclofenac versus carrier

Outcome: 5 Withdrawals due to adverse events

Studyorsubgroup Diclofenac Carrier RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI 108-97 10/198 4/187 6.5 % 2.36 [ 0.75, 7.40 ]

Altman 2009 9/107 9/109 14.0 % 1.02 [ 0.42, 2.47 ]

Baer 2005 39/721 18/705 28.6 % 2.12 [ 1.22, 3.67 ]

Baraf 2011 5/84 3/80 4.8 % 1.59 [ 0.39, 6.43 ]

Bookman 2004 1/51 2/52 3.1 % 0.51 [ 0.05, 5.45 ]

Bruhlmann 2003 0/78 1/77 2.4 % 0.33 [ 0.01, 7.96 ]

Dreiser 1993 0/30 0/30 Not estimable

Galeazzi 1993 1/38 0/36 0.8 % 2.85 [ 0.12, 67.68 ]

Grace 1999 2/117 0/120 0.8 % 5.13 [ 0.25, 105.67 ]

Niethard 2005 8/164 4/162 6.3 % 1.98 [ 0.61, 6.43 ]

Roth 2004 16/154 18/157 28.0 % 0.91 [ 0.48, 1.71 ]

Simon 2009 7/48 3/47 4.8 % 2.28 [ 0.63, 8.31 ] Total (95% CI) 1790 1762 100.0 % 1.55 [ 1.14, 2.11 ] Total events: 98 (Diclofenac), 62 (Carrier) Heterogeneity: Chi2 = 8.38, df = 10 (P = 0.59); I2 =0.0% Test for overall effect: Z = 2.81 (P = 0.0050) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours diclofenac Favours carrier

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 78 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 1.6. Comparison 1 Topical diclofenac versus carrier, Outcome 6 Withdrawals due to lack of efﬁcacy.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 1 Topical diclofenac versus carrier

Outcome: 6 Withdrawals due to lack of efﬁcacy

Studyorsubgroup Diclofenac Carrier RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Altman 2009 8/198 13/187 8.2 % 0.58 [ 0.25, 1.37 ]

Baer 2005 8/107 18/109 10.9 % 0.45 [ 0.21, 1.00 ]

Baraf 2011 32/721 51/705 31.6 % 0.61 [ 0.40, 0.94 ]

Bookman 2004 2/84 8/80 5.0 % 0.24 [ 0.05, 1.09 ]

Bruhlmann 2003 1/51 2/52 1.2 % 0.51 [ 0.05, 5.45 ]

Dreiser 1993 0/78 9/77 5.9 % 0.05 [ 0.00, 0.88 ]

Galeazzi 1993 0/30 0/30 Not estimable

Grace 1999 0/38 0/36 Not estimable

Niethard 2005 1/117 0/120 0.3 % 3.08 [ 0.13, 74.76 ]

Roth 2004 28/164 42/162 25.9 % 0.66 [ 0.43, 1.01 ]

Simon 2009 16/154 18/155 11.0 % 0.89 [ 0.47, 1.69 ] Total (95% CI) 1742 1713 100.0 % 0.59 [ 0.47, 0.75 ] Total events: 96 (Diclofenac), 161 (Carrier) Heterogeneity: Chi2 = 7.62, df = 8 (P = 0.47); I2 =0.0% Test for overall effect: Z = 4.34 (P = 0.000014) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours diclofenac Favours carrier

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 79 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.1. Comparison 2 Topical ketoprofen versus carrier, Outcome 1 Clinical success.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 2 Topical ketoprofen versus carrier

Outcome: 1 Clinical success

Studyorsubgroup Ketoprofen Carrier OddsRatio Weight Odds Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

1 Duration 6 to 12 weeks Conaghan 2013 (1) 205/453 192/472 44.4 % 1.21 [ 0.93, 1.56 ]

Kneer 2013 (2) 562/638 147/190 11.6 % 2.16 [ 1.43, 3.28 ]

Rother 2007 64/138 35/127 8.4 % 2.27 [ 1.36, 3.80 ]

Rother 2013 113/274 142/281 35.5 % 0.69 [ 0.49, 0.96 ] Subtotal (95% CI) 1503 1070 100.0 % 1.22 [ 1.03, 1.45 ] Total events: 944 (Ketoprofen), 516 (Carrier) Heterogeneity: Chi2 = 24.19, df = 3 (P = 0.00002); I2 =88% Test for overall effect: Z = 2.28 (P = 0.023) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours carrier Favours ketoprofen

(1) 100 mg and 200 mg daily doses combined

(2) 50 mg, 100 mg, and 200 mg daily doses combined

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 80 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.2. Comparison 2 Topical ketoprofen versus carrier, Outcome 2 Local adverse events.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 2 Topical ketoprofen versus carrier

Outcome: 2 Local adverse events

Studyorsubgroup Ketoprofen Carrier RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Conaghan 2013 41/463 40/472 24.7 % 1.04 [ 0.69, 1.58 ]

Kneer 2013 127/667 39/199 37.4 % 0.97 [ 0.70, 1.34 ]

Rother 2007 39/138 28/127 18.2 % 1.28 [ 0.84, 1.95 ]

Rother 2013 29/274 32/281 19.7 % 0.93 [ 0.58, 1.49 ] Total (95% CI) 1542 1079 100.0 % 1.04 [ 0.85, 1.27 ] Total events: 236 (Ketoprofen), 139 (Carrier) Heterogeneity: Chi2 = 1.33, df = 3 (P = 0.72); I2 =0.0% Test for overall effect: Z = 0.37 (P = 0.71) Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2 Favours ketoprofen Favours carrier

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 81 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.3. Comparison 2 Topical ketoprofen versus carrier, Outcome 3 Gastrointestinal adverse events.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 2 Topical ketoprofen versus carrier

Outcome: 3 Gastrointestinal adverse events

Studyorsubgroup Ketoprofen Carrier RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Conaghan 2013 (1) 40/463 40/472 58.3 % 1.02 [ 0.67, 1.55 ]

Kneer 2013 (2) 22/667 9/199 20.4 % 0.73 [ 0.34, 1.56 ]

Rother 2007 13/138 12/127 18.4 % 1.00 [ 0.47, 2.10 ]

Rother 2013 2/274 2/281 2.9 % 1.03 [ 0.15, 7.23 ] Total (95% CI) 1542 1079 100.0 % 0.96 [ 0.69, 1.32 ] Total events: 77 (Ketoprofen), 63 (Carrier) Heterogeneity: Chi2 = 0.60, df = 3 (P = 0.90); I2 =0.0% Test for overall effect: Z = 0.27 (P = 0.79) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours ketoprofen Favours carrier

(1) 100 mg and 200 mg daily doses combined

(2) 50 mg, 100 mg, and 200 mg daily doses combined

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 82 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.4. Comparison 2 Topical ketoprofen versus carrier, Outcome 4 Withdrawals due to adverse events.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 2 Topical ketoprofen versus carrier

Outcome: 4 Withdrawals due to adverse events

Studyorsubgroup Ketoprofen Carrier RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Conaghan 2013 (1) 16/463 15/472 24.8 % 1.09 [ 0.54, 2.17 ]

Kneer 2013 (2) 40/667 8/199 20.6 % 1.49 [ 0.71, 3.13 ]

Rother 2007 23/138 20/127 34.8 % 1.06 [ 0.61, 1.83 ]

Rother 2013 20/274 12/281 19.8 % 1.71 [ 0.85, 3.43 ] Total (95% CI) 1542 1079 100.0 % 1.28 [ 0.92, 1.78 ] Total events: 99 (Ketoprofen), 55 (Carrier) Heterogeneity: Chi2 = 1.50, df = 3 (P = 0.68); I2 =0.0% Test for overall effect: Z = 1.49 (P = 0.14) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours ketoprofen Favours carrier

(1) 100 mg and 200 mg daily doses combined

(2) 50 mg, 100 mg, and 200 mg daily doses combined

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 83 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 2.5. Comparison 2 Topical ketoprofen versus carrier, Outcome 5 Withdrawals due to lack of efﬁcacy.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 2 Topical ketoprofen versus carrier

Outcome: 5 Withdrawals due to lack of efﬁcacy

Studyorsubgroup Ketoprofen Carrier RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Conaghan 2013 (1) 11/463 13/472 20.6 % 0.86 [ 0.39, 1.91 ]

Kneer 2013 (2) 35/463 35/667 45.9 % 1.44 [ 0.92, 2.27 ]

Rother 2007 1/138 3/127 5.0 % 0.31 [ 0.03, 2.91 ]

Rother 2013 16/274 18/281 28.5 % 0.91 [ 0.47, 1.75 ] Total (95% CI) 1338 1547 100.0 % 1.11 [ 0.80, 1.55 ] Total events: 63 (Ketoprofen), 69 (Carrier) Heterogeneity: Chi2 = 3.26, df = 3 (P = 0.35); I2 =8% Test for overall effect: Z = 0.64 (P = 0.52) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours ketoprofen Favours carrier

(1) 100 mg and 200 mg daily doses combined

(2) 50 mg, 100 mg, and 200 mg daily doses combined

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 84 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.1. Comparison 3 Topical NSAID versus oral NSAID, Outcome 1 Clinical success.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 3 Topical NSAID versus oral NSAID

Outcome: 1 Clinical success

Studyorsubgroup TopicalNSAID OralNSAID RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Dickson 1991 75/117 71/118 15.2 % 1.07 [ 0.87, 1.30 ]

Rother 2007 68/138 51/132 11.2 % 1.28 [ 0.97, 1.68 ]

Simon 2009 73/154 77/151 16.7 % 0.93 [ 0.74, 1.17 ]

Tugwell 2004 201/303 210/301 45.2 % 0.95 [ 0.85, 1.06 ]

Zacher 2001 66/165 53/156 11.7 % 1.18 [ 0.88, 1.57 ] Total (95% CI) 877 858 100.0 % 1.03 [ 0.95, 1.12 ] Total events: 483 (Topical NSAID), 462 (Oral NSAID) Heterogeneity: Chi2 = 6.05, df = 4 (P = 0.20); I2 =34% Test for overall effect: Z = 0.64 (P = 0.53) Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2 Favours oral NSAID Favours topical NSAID

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 85 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.2. Comparison 3 Topical NSAID versus oral NSAID, Outcome 2 Local adverse events.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 3 Topical NSAID versus oral NSAID

Outcome: 2 Local adverse events

Studyorsubgroup TopicalNSAID OralNSAID RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Dickson 1991 3/117 4/118 8.3 % 0.76 [ 0.17, 3.31 ]

Rother 2007 39/138 27/132 57.7 % 1.38 [ 0.90, 2.12 ]

Sandelin 1997 16/126 1/82 2.5 % 10.41 [ 1.41, 77.02 ]

Simon 2009 41/154 11/151 23.2 % 3.65 [ 1.95, 6.84 ]

Tugwell 2004 83/311 4/322 8.2 % 21.48 [ 7.97, 57.88 ] Total (95% CI) 846 805 100.0 % 3.74 [ 2.76, 5.06 ] Total events: 182 (Topical NSAID), 47 (Oral NSAID) Heterogeneity: Chi2 = 38.18, df = 4 (P<0.00001); I2 =90% Test for overall effect: Z = 8.54 (P < 0.00001) Test for subgroup differences: Not applicable

0.02 0.1 1 10 50 Favours topical NSAID Favours oral NSAID

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 86 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.3. Comparison 3 Topical NSAID versus oral NSAID, Outcome 3 Gastrointestinal adverse events.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 3 Topical NSAID versus oral NSAID

Outcome: 3 Gastrointestinal adverse events

Studyorsubgroup TopicalNSAID OralNSAID RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Dickson 1991 15/117 11/118 4.4 % 1.38 [ 0.66, 2.87 ]

Rother 2007 13/138 18/132 7.3 % 0.69 [ 0.35, 1.35 ]

Sandelin 1997 6/126 11/82 5.3 % 0.35 [ 0.14, 0.92 ]

Simon 2009 10/154 36/151 14.4 % 0.27 [ 0.14, 0.53 ]

Tugwell 2004 108/311 150/311 59.6 % 0.72 [ 0.59, 0.87 ]

Zacher 2001 15/165 22/156 9.0 % 0.64 [ 0.35, 1.20 ] Total (95% CI) 1011 950 100.0 % 0.66 [ 0.56, 0.77 ] Total events: 167 (Topical NSAID), 248 (Oral NSAID) Heterogeneity: Chi2 = 13.17, df = 5 (P = 0.02); I2 =62% Test for overall effect: Z = 5.02 (P < 0.00001) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours topical NSAID Favours oral NSAID

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 87 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.4. Comparison 3 Topical NSAID versus oral NSAID, Outcome 4 Withdrawals due to adverse events.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 3 Topical NSAID versus oral NSAID

Outcome: 4 Withdrawals due to adverse events

Studyorsubgroup TopicalNSAID OralNSAID RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI

Dickson 1991 9/117 7/118 4.9 % 1.30 [ 0.50, 3.37 ]

Rother 2007 23/138 18/132 13.0 % 1.22 [ 0.69, 2.16 ]

Sandelin 1997 4/126 1/82 0.9 % 2.60 [ 0.30, 22.88 ]

Simon 2009 16/154 19/151 13.6 % 0.83 [ 0.44, 1.54 ]

Tugwell 2004 64/311 79/311 55.9 % 0.81 [ 0.61, 1.08 ]

Zacher 2001 5/165 16/156 11.6 % 0.30 [ 0.11, 0.79 ] Total (95% CI) 1011 950 100.0 % 0.85 [ 0.68, 1.06 ] Total events: 121 (Topical NSAID), 140 (Oral NSAID) Heterogeneity: Chi2 = 7.92, df = 5 (P = 0.16); I2 =37% Test for overall effect: Z = 1.48 (P = 0.14) Test for subgroup differences: Not applicable

0.1 0.2 0.5 1 2 5 10 Favours topical NSAD Favours oral NSAID

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 88 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Analysis 3.5. Comparison 3 Topical NSAID versus oral NSAID, Outcome 5 Withdrawals due to lack of efﬁcacy.

Review: Topical NSAIDs for chronic musculoskeletal pain in adults

Comparison: 3 Topical NSAID versus oral NSAID

Outcome: 5 Withdrawals due to lack of efﬁcacy

Studyorsubgroup TopicalNSAID OralNSAID RiskRatio Weight Risk Ratio n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI Rother 2007 1/138 3/132 16.9 % 0.32 [ 0.03, 3.03 ]

Simon 2009 16/154 5/151 27.9 % 3.14 [ 1.18, 8.35 ]

Tugwell 2004 28/311 10/311 55.2 % 2.80 [ 1.38, 5.67 ] Total (95% CI) 603 594 100.0 % 2.47 [ 1.45, 4.22 ] Total events: 45 (Topical NSAID), 18 (Oral NSAID) Heterogeneity: Chi2 = 3.53, df = 2 (P = 0.17); I2 =43% Test for overall effect: Z = 3.33 (P = 0.00087) Test for subgroup differences: Not applicable

0.01 0.1 1 10 100 Favours topical NSAID Favours oral NSAID

APPENDICES

Appendix 1. CENTRAL search strategy 1. MeSH descriptor Anti-inflammatory Agents, non-steroidal/ (13421) 2. (bufexamac OR bufexine OR calmaderm OR ekzemase OR dicoflenac OR solaraze OR pennsaid OR voltarol OR emulgel OR voltarene OR optha OR voltaren OR etofenamate OR afrolate OR algesalona OR bayro OR deiron OR etofen OR flexium OR flogoprofen OR rheuma-gel OR rheumon OR traumalix OR traumon OR zenavan OR felbinac OR dolinac OR flexfree OR napageln OR target OR traxam OR fentiazac OR domureuma OR fentiazaco OR norvedan OR riscalon OR fepradinol OR dalgen OR flexidol OR cocresol OR rangozona OR reuflodol OR pinazone OR zepelin OR flufenamic OR dignodolin OR rheuma OR lindofluid OR sastridex OR lunoxaprofen OR priaxim OR flubiprofen OR fenomel OR ocufen OR ocuflur OR “Trans Act LAT” OR tulip OR ibuprofen OR cuprofen OR “deep relief” OR fenbid OR ibu-cream OR ibugel OR ibuleve OR ibumousse OR ibuspray OR “nurofen gel” OR proflex OR motrin OR advil OR radian OR ralgex OR ibutop OR indomethacin OR indocin OR indospray OR isonixin OR nixyn OR ketoprofen OR tiloket OR oruvail OR powergel OR solpaflex OR ketorolac OR acular OR trometamol OR meclofenamic OR naproxen OR naprosyn OR niflumic OR actol OR flunir OR niflactol topico OR niflugel OR nifluril OR oxyphenbutazone OR californit OR diflamil OR otone OR tanderil OR piketoprofen OR calmatel OR triparsean OR piroxicam OR feldene OR pranoprofen OR oftalar OR pranox OR suxibuzone OR danilon OR flamilon OR ufenamate OR fenazol):ti,ab,kw. (24140) 3. 1 OR 2 (32382) 4. MeSH descriptor Administration, Topical/ (12177)

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 89 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. 5. (topical* OR cutaneous OR dermal OR transcutaneous OR transdermal OR percutaneous OR skin OR massage OR embrocation OR gel OR ointment OR aerosol OR cream OR creme OR lotion OR mousse OR foam OR liniment OR spray OR rub OR balm OR salve OR emulsion OR oil OR patch OR plaster):ti,ab,kw. (69415) 6. 4 OR 5 (71972) 7. (pain OR painful OR analgesi*):ti,ab,kw. (76989) 8. MeSH DESCRIPTOR pain EXPLODE ALL TREES (29985) 9. 7 or 8 (82235) 10. 3 AND 6 AND 9 (1163) 11. 2012 TO 2015:YR (111751) 12. 10 AND 11 (179) 13. To update

Appendix 2. MEDLINE search strategy (via OVID) 1. exp Anti-inflammatory Agents, non-steroidal/ (19443) 2. (bufexamac OR bufexine OR calmaderm OR ekzemase OR dicoflenac OR solaraze OR pennsaid OR voltarol OR emulgel OR voltarene OR optha OR voltaren OR etofenamate OR afrolate OR algesalona OR bayro OR deiron OR etofen OR flexium OR flogoprofen OR rheuma-gel OR rheumon OR traumalix OR traumon OR zenavan OR felbinac OR dolinac OR flexfree OR napageln OR target OR traxam OR fentiazac OR domureuma OR fentiazaco OR norvedan OR riscalon OR fepradinol OR dalgen OR flexidol OR cocresol OR rangozona OR reuflodol OR pinazone OR zepelin OR flufenamic OR dignodolin OR rheuma OR lindofluid OR sastridex OR lunoxaprofen OR priaxim OR flubiprofen OR fenomel OR ocufen OR ocuflur OR “Trans Act LAT” OR tulip OR ibuprofen OR cuprofen OR “deep relief” OR fenbid OR ibu-cream OR ibugel OR ibuleve OR ibumousse OR ibuspray OR “nurofen gel” OR proflex OR motrin OR advil OR radian OR ralgex OR ibutop OR indomethacin OR indocin OR indospray OR isonixin OR nixyn OR ketoprofen OR tiloket OR oruvail OR powergel OR solpaflex OR ketorolac OR acular OR trometamol OR meclofenamic OR naproxen OR naprosyn OR niflumic OR actol OR flunir OR niflactol topico OR niflugel OR nifluril OR oxyphenbutazone OR californit OR diflamil OR otone OR tanderil OR piketoprofen OR calmatel OR triparsean OR piroxicam OR feldene OR pranoprofen OR oftalar OR pranox OR suxibuzone OR danilon OR flamilon OR ufenamate OR fenazol).mp. (135055) 3. 1 OR 2 (149887) 4. exp Administration, Topical/ (9882) 5. (topical* OR cutaneous OR dermal OR transcutaneous OR transdermal OR percutaneous OR skin OR massage OR embrocation OR gel OR ointment OR aerosol OR cream OR creme OR lotion OR mousse OR foam OR liniment OR spray OR rub OR balm OR salve OR emulsion OR oil OR patch OR plaster).mp. (183886) 6. 4 OR 5 (186650) 7. exp Musculoskeletal diseases/ (109780) 8. (arthrit* OR rhemat* or osteoarth* OR tend?nitis OR sciatica OR lumbago OR fibrositis*).mp. (32728) 9. 7 OR 8 (115939) 10. Chronic Pain/ (4060) 11. (pain OR painful OR analgesi*).mp. (97784) 12. 10 OR 11 (97784) 13. randomized controlled trial.pt. (79001) 14. controlled clinical trial.pt. (6294) 15. randomized.ab. (70728) 16. placebo.ab. (25005) 17. drug therapy.fs. (291957) 18. randomly.ab. (45688) 19. trial.ab. (71983) 20. groups.ab. (257513) 21. OR/13-20 (603334) 22. 3 AND6 AND9 AND12 AND21(115) 23. Limit 22 to yr=“2012-Current” (90)

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 90 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Appendix 3. EMBASE search strategy 1. exp nonsteroid antiinflammatory agent/ (320629) 2. (bufexamac OR bufexine OR calmaderm OR ekzemase OR dicoflenac OR solaraze OR pennsaid OR voltarol OR emulgel OR voltarene OR optha OR voltaren OR etofenamate OR afrolate OR algesalona OR bayro OR deiron OR etofen OR flexium OR flogoprofen OR rheuma-gel OR rheumon OR traumalix OR traumon OR zenavan OR felbinac OR dolinac OR flexfree OR napageln OR target OR traxam OR fentiazac OR domureuma OR fentiazaco OR norvedan OR riscalon OR fepradinol OR dalgen OR flexidol OR cocresol OR rangozona OR reuflodol OR pinazone OR zepelin OR flufenamic OR dignodolin OR rheuma OR lindofluid OR sastridex OR lunoxaprofen OR priaxim OR flubiprofen OR fenomel OR ocufen OR ocuflur OR “Trans Act LAT” OR tulip OR ibuprofen OR cuprofen OR “deep relief” OR fenbid OR ibu-cream OR ibugel OR ibuleve OR ibumousse OR ibuspray OR “nurofen gel” OR proflex OR motrin OR advil OR radian OR ralgex OR ibutop OR indomethacin OR indocin OR indospray OR isonixin OR nixyn OR ketoprofen OR tiloket OR oruvail OR powergel OR solpaflex OR ketorolac OR acular OR trometamol OR meclofenamic OR naproxen OR naprosyn OR niflumic OR actol OR flunir OR niflactol topico OR niflugel OR nifluril OR oxyphenbutazone OR californit OR diflamil OR otone OR tanderil OR piketoprofen OR calmatel OR triparsean OR piroxicam OR feldene OR pranoprofen OR oftalar OR pranox OR suxibuzone OR danilon OR flamilon OR ufenamate OR fenazol).mp. (667855) 3. 1 OR 2 (911117) 4. exp topical drug administration/ (14839) 5. (topical* OR cutaneous OR dermal OR transcutaneous OR transdermal OR percutaneous OR skin OR massage OR embrocation OR gel OR ointment OR aerosol OR cream OR creme OR lotion OR mousse OR foam OR liniment OR spray OR rub OR balm OR salve OR emulsion OR oil OR patch OR plaster).mp. (1268303) 6. 4 OR 5 (1268303) 7. exp musculoskeletal disease/ (1087620) 8. (arthrit* OR rhemat* or osteoarth* OR tend?nitis OR sciatica OR lumbago OR fibrositis*).mp. (232138) 9. 7 OR 8 (1104767) 10. chronic pain/ (33061) 11. (pain OR painful OR analgesi*).mp. (742030) 12. 10 OR 11 (742030) 13. clinical trial.sh. (692438) 14. controlled clinical trial.sh. (344474) 15. randomized controlled trial.sh. (314236) 16. double-blind procedure.sh. (93716) 17. (clin* adj25 trial*).ab. (303361) 18. ((doubl* or trebl* or tripl*) adj25 (blind* or mask*)).ab. (102398) 19. placebo*.ab. (159368) 20. random*.ab. (791695) 21. OR/13-20 (1460942) 22. 3 AND6 AND9 AND12 AND21(2317) 23. Limit 24 to yr=“2012-Current” (327)

Appendix 4. GRADE: criteria for assigning grade of evidence The GRADE system uses the following criteria for assigning grade of evidence (GRADEpro GDT 2015). • High = further research is very unlikely to change our confidence in the estimate of effect. • Moderate = further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. • Low = further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. • Very low = any estimate of effect is very uncertain.

We decrease grade if we ﬁnd: • a serious (-1) or very serious (-2) limitation to study quality; • important inconsistency (-1); • some (-1) or major (-2) uncertainty about directness;

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 91 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. • imprecise or sparse data (-1); • a high probability of reporting bias (-1).

Appendix 5. Unpublished studies

NCT number Preparation Date of completion Number of participants Sponsor * identiﬁed in earlier review

NCT00108992 Diclofenac, solution and September 2005 OA knee (ﬂare) Nuvo Research Inc tablet (DD) 750

NCT00171652 Diclofenac sodium gel October 2005 OA hand Novartis 1% (included in Barthel 360 2010)

NCT00211549* Ketoprofen (IDEA-033) Veriﬁed complete in OA knee IDEA AG March 2009 875

NCT00265304* Ketoprofen (IDEA-033) July 2007 OA knee IDEA AG some patients from 550 NCT00211549

NCT00365586* Ketoprofen patch April 2007 OA knee (ﬂare) Endo Pharmaceuticals 300

NCT00484120* Diclofenac 3% nano- November 2008 OA knee Pharmos emulsion cream 123

NCT00546507* Diclofenac sodium 4% October 2008 OA knee (ﬂare) Mika Pharma GmbH spray 650

NCT00546832* Diclofenac sodium 4% November 2008 OA knee (ﬂare) Mika Pharma GmbH spray 650

NCT00647231* Ketoprofen patch August 2008 OA knee Hisamitsu Pharmaceuti- (HKT-500) 300 cal Co., Inc

NCT00792727* Ketoprofen patch May 2008 OA knee Hisamitsu Pharmaceuti- (HKT-500) 380 cal Co., Inc

NCT01119898* Diclofenac sodium 2.0% March 2011 OA knee (ﬂare) Mallinckrodt (PENNSAID) 260

NCT01456611* Diclofenac sodium 1% April 2012 OA knee Anchen gel (Anchen versus No- 749 Pharmaceuticals, Inc vartis)

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 92 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Appendix 6. Summary of results in individual studies - efﬁcacy

Summary of outcomes: successful treatment

Study ID Treatment Deﬁnition of clinical Number with success- Secondary measures response ful outcome Study duration

102-93-1 (1) Diclofenac solution 6 weeks No dichotomous out- Mean pain-relief-level (with 45.5% DMSO; comes reported days: (1) > (2) > (3) Pennsaid®) (2) Control (with 45.5% DMSO) (3) Placebo (with 4.55% DMSO) Solution applied as 40 drops (about 1 mL) x 4 daily Number of participants in each group not reported

108-97 (1) Diclofenac solution 6 weeks No dichotomous out- (1) had greatest im- (with 45.5% DMSO; comes reported provement in pain score, Pennsaid®), n = 48 but differences between (2) Control (with 45.5% groups were not statisti- DMSO), n = 47 cally signiﬁcant (3) Diclofenac solution (with 2.3% DMSO), n = 50 (4) Placebo (with 2.3% DMSO), n = 50 Solution applied 4 x daily to maximum 40 drops per hand

Altman 2009 (1) Diclofenac sodium OARSI response in OARSI responder: PGE: very good or excel- gel 1% (Voltaren) with dominant hand (1) 65.7% = 130/198 lent vehicle 2 g, n = 198 PGE 5-point scale (2) 56.7% = 106/187 (1) 47.7% = 93/195 (2) Placebo gel (vehicle 8 weeks (2) 36.5% = 66/185 carrier) n = 187 Gels applied x 4 daily

Baer 2005 (1) Diclofenac sodium 1. Participants with ≥ 50% ≥ 50% PR: PGE: good or very good 5% (with 45. PR (provided by author) (1) 46/105 (1) 46/105 5% DMSO; Pennsaid®) (2) 27/107 (2) 18/107 , n = 107 PGE 5-point scale OMERACT-OARSI re- (2) Placebo (vehicle car- sponder (post hoc) rier), n = 109 6 weeks (1) 69/105 Solution applied as 40

drops x 4 daily (2) 53/107

Signiﬁcant improvement in score with topical diclofenac for pain, physical function, PGE, and stiffness at 6 weeks

Balthazar-Letawe 1987 (1) Diclofenac (Voltaren 2 weeks No dichotomous out- No data Emulgel), n = 25 comes reported (2) Indomethacin (Indo- cid) gel, n = 25 Gels applied x 2 daily

Baraf 2011 (1) Diclofenac sodium OARSI response in OARSI: PGE: very good, excel- gel 1%, n = 721 treated knee (using pain (1) 461/719 lent (2) Placebo gel (vehicle on movement) (2) 394/705 (1) 344/719 only), n = 705 PGE 5-point scale (2) 266/705 Medication applied 4 x 4 12 weeks g daily

Bolten 1991 (1) Felbinac gel 3% 1 g, Pain on rest: 5-point Spontaneous pain (+3 or Mean change in pain at n = 142 scale (-1 to +3 where + = +2): rest or activity signiﬁ- (2) Placebo gel, n = 139 improvement) (1) 34/142 cantly improved after 14 Gel applied x 3 daily (2) 15/139 days in (1) 2 weeks

Bookman 2004 (1) Diclofenac solution Participants with ≥ 50% ≥ 50% PR: Pain on walking at 4 1.5% in DMSO (45. PR (from author) (1) 44/84 weeks (4-point scale): 5%: Pennsaid®), n = 84 4 weeks (2) 26/79 (1) 1.0 (SD 1.0) (2) Carrier with DMSO (3) no data (2) 1.5 (SD 1.1) (45.5%), n = 80 (3) Carrier with 1/10th Mean change in pain, DMSO (4.55%), n = 84 physical function, stiff- Solution applied as 40 ness, pain on walking, drops (= 1.3 mL) x 4 and PGE score all statis- daily tically better for (1) than (2) or (3)

Mean paracetamol con- sumption less in (1) than (2) or (3)

Bruhlmann 2003 (1) Diclofenac sodium PGE 5-point scale PGE excellent: Num- patch 1% (180 mg; Flec- 2 weeks (1) 12/51 ber of patients judging tor-EP), n = 51 (2) 4/52 the treatment group “no (2) Placebo patch, n = 52 efﬁcacy”: Patch applied x 2 daily (1) 5/51 (2) 9/52

Signiﬁcantly greater reduction in mean spontaneous pain with (1) than (2) on day 7 and 14 There was a signiﬁcant difference between treatment group and baseline at all 3 visits

Burgos 2001 (1) Flurbiprofen LAT (= Undefined improve- Improved: Patients showed a sig- 40 mg) + placebo cream, ment: “Do you think (1) 80% = 46/58 nificant mean improve- n = 64 that the treatment ap- (2) 65% = 39/60 ment in all clinical pa- (2) Piketoprofen cream plied relieved the pain?” rameters assessed: sever- 1.8% (4 cm ~ 36 mg) + 2 weeks ity of disease, sponta- placebo patch, n = 65 neous pain, tenderness, Patch applied x 2 daily, and mobility of the in- cream x 3 daily volved joints, although no statistically significant differences between the 2 groups

Conaghan 2013 (1) Ketoprofen (IDEA- Participants with ≥ 50% ≥ 50% PR: Mean PI reduction from 033) gel 100 mg daily, n PR (1) 105/233 baseline 1.9 (SD 1.6), = 233 12 weeks (2) 100/230 ~39%) in all groups ex- (2) Ketoprofen (IDEA- (3) 97/238 cept oral placebo (1.4 033) gel 200 mg daily, n (4) 95/234 (SD 1.6), 29%) = 230 (5) 100/233 Mean change from base- (3) 4.4 g vehicle daily, n (6) 67/227 line in physical function = 238 was similar for all treat- (4) 8.8 g vehicle daily, n ment groups except oral = 235 placebo (5) Oral celecoxib 200 mg daily. N = 235 (6) Oral placebo, n = 228 All medication administered in divided daily dose (vehicle = TDT-064)

Dickson 1991 (1) Piroxicam gel 0.5% PGE 4-point scale PGE excellent or good: Mean reduction in pain (1 g = 5 mg piroxicam) + 4 weeks (1) 64% = 75/117 and improvement placebo tablet, n = 117 (2) 60% = 71/118 in ability to perform task (2) Ibuprofen tablet 400 for all arthritic symp- mg + placebo cream, n = toms - difference not sig- 118 niﬁcant between gel and mg x 3 daily, n = 118 oral groups Gels applied x 3 daily, tablet taken x 3 daily

Dreiser 1993 (1) Diclofenac (DHEP) PGE 5-point scale PGE excellent or good: (1) signiﬁcantly better patch (= 180 mg), n = 78 4 weeks (1) 55/78 than (2) for group mean (2) Placebo patch, n = 77 (2) 21/77 spontaneous pain from Patch applied x 2 daily 4th day on

Ergun 2007 (1) Nimesulide gel 1% PGE 5-point scale PGE very effective or ef- (1) (Sulidin) 0.4 mg/10 cm 4 weeks fective: signiﬁcantly better than 2, n = 51 (1) 23/49 (2) for mean change in (2) Placebo gel, n = 23 (2) 2/21 overall WOMAC score Gels applied x 3 daily over 30 days, but individual components did not reach statistical sig- niﬁcance

Galeazzi 1993 (1) Diclofenac (DHEP) No patient-reported di- No data (1) better than (2) for plaster (= 180 mg dichotomous outcomes pain on pressure after 5 clofenac derivative), n = 2 weeks days 30 (2) Placebo plaster, n = 30 Plasters applied x 2 daily

Grace 1999 (1) Diclofenac (with PGE 4-point scale PGE mild or none: Non- lecithin) gel 2% (2.5 g), 2 weeks (1) 12/38 signiﬁcant difference be- n = 38 (2) 9/36 tween 2 trial groups (2) Placebo gel, n = 36 at baseline and post Gels applied as one treatment on aggregated scoop 3 x daily WOMAC and pain subscale scores (pain, stiffness, physical function) . (1) signiﬁcantly better than (2) for improvement in WOMAC pain subscale

Gui 1982 (1) Ibuprofen cream, n = Undeﬁned improvement With movement: (1) 20 (strength, dose, quan- in pain (1) 14/18 signiﬁcantly better than tity not reported) 3 weeks (2) 7/19 (2) for mean improve- (2) Placebo cream, n = 20 With pressure: ment in pain (sponta- Creams applied x 2 daily (1) 15/20 neous, movement, pres- (2) 7/20 sure) and functional in- capacity

Hohmeister 1983 (1) Flufenamate 3% plus PGE PGE very good or good: - salicylate 2% gel (Mobil- 3 weeks (1) 44/49 isin), n = 49 (quantity (2) 4/51 not reported) (2) Placebo gel, n = 51 Gels applied x 3 daily

Kneer 2013 (1) Ketoprofen (IDEA- OMERACT/OARSI re- OMERACT/OARSI PGE - group mean data 033) gel 50 mg daily, n = sponse (ITT) only. No clinically rele- 223 12 weeks (1) 88.6% = 190/214 vant differences at week (2) Ketoprofen (IDEA- (2) 86.8% = 185/213 12 033) gel 100 mg daily, n (3) 88.6% = 187/211 Mean PI reduction from = 223 (4) 77.5% = 147/190 baseline (3) Ketoprofen (IDEA- (1) 34/100 033) gel 200 mg daily, n (2) 37/100 = 221 (3) 37/100 (4) Vehicle, n = 199 (4) 33/100 All medication administered in divided daily dose

Link 1996 (1) Ketoprofen gel 2.5%, No patient-reported di- No data - n = 56 chotomous outcomes (2) Placebo gel, n = 59 2 weeks Gels applied as 4 to 10 cm strip x 3 or 4 daily

McCleane 2000 (1) Piroxicam gel 2.5%, Participants with ≥ 50% ≥ 50% PR: Signiﬁcant reduction in n = 40 relief of pain (1) 1/40 mean pain scores in (2) GTN 1%, n = 36 4 weeks (2) 4/36 group (4), with no fall in (3) Piroxicam gel 2.5%/ (3) 7/37 the placebo and piroxi- GTN 1%, n = 37 (4) 4/46 cam groups (this is prob- (4) Placebo gel, n = 46 ably relative to baseline Gels applied as “small as opposed to head-to- volume” x 3 daily head comparison)

NCT01980940 (1) Etoricoxib gel 50 mg, PGE 5-point scale PGE of treatment, well No 4% DMSO, n = 24 2 weeks or very well: signiﬁcant difference be- (2) Placebo gel, n = 24 (1) 13/24 tween groups for change (2) 14/24 in mean WOMAC pain score, function, or stiffness

Niethard 2005 (1) Diclofenac 1.16% gel PGE 5-point scale PGE excellent or very OMERACT-OARSI re- (Voltaren Emulgel), n = 3 weeks good: sponder at end of trial 117 (1) 36/117 (1) 73/117 (2) Placebo gel, n = 121 (2) 24/120 (2) 46/120 Gels applied 4 g x 4 daily

Ottillinger 2001 (1) Eltenac gel 1% 3 g, n PGE (no details of scale) No useable data Patient-reported global = 57 4 weeks efﬁcacy did not differ be- (2) Eltenac gel 0.3% 3 g, tween treatments n = 59 Measurement of global (3) Eltenac gel 0.1% 3 g, pain on VAS showed no n = 59 signiﬁcant difference for (4) Placebo gel, n = 59

Gels applied as 4 inch eltenac versus placebo string (approx 3 g) x 3 daily; to give 9 mg, 27 mg, 90 mg daily doses, or placebo

Poul 1993 (1) Flurbiprofen LAT Participants’ overall effi- No useable data There were statistically patch, 40 mg, n = 53 cacy estimates. significant differences in (2) Placebo patch, n = 51 2 weeks favour of flurbiprofen Medication applied as LAT at both days 7 + patch x 2 daily 14 for the investigators’ overall opinion of sever- ity of condition

Participant-reported night pain, quality of sleep, day pain not signiﬁcantly different between 2 treatment groups

Rose 1991 Piroxicam gel 5% (5 mg) PGE 4-point scale PGE excellent: - , n = 15 2 weeks (1) 8/15 Placebo gel, n = 15 (2) 8/15 Gels applied 1 mg x 4 daily

Roth 1995 Diclofenac 3% Participant No useable data Analgesic effect of di- + hyaluron 2.5% gel, n = estimate of overall pain, clofenac gel was sig- 59 5-point scale niﬁcantly greater than Placebo + hyaluron 2. 2 weeks placebo at week 2 5% gel, n = 60 Gels applied 2 g x 4 daily

Roth 2004 (1) Diclofenac Participants with ≥ 50% ≥ 50% PR: Mean change in pain, 1.5% with DMSO (45. PR (from author) (1) 79/163 physical function, stiff- 5%; Pennsaid®), n = 6 weeks (2) 55/159 ness and PGE all statis- 164 tically better for (1) than (2) Carrier with DMSO (2) and also for pain on (45.5%), n = 162 walking Solution applied as 40 drops x 4 daily

Rother 2007 (1) Ketoprofen PGE 5-point scale PGE excellent or good: Mean change in pain, gel (IDEA-33) 110 mg + 6 weeks (1) 64/138 but not physical func- placebo tabs, n = 138 (2) 51/132 tion statistically better (2) Celecoxib tabs 100 (3) 35/127 for (1) than (3) in ITT mg + placebo gel, n = 132 analysis. Both signiﬁ- (3) Placebo gel and tabs, cantly better in PP anal-

n = 127 ysis Gel applied x 2 daily, (2) better than (3) for tablet taken x 2 daily both

Rother 2013 (1) Ketoprofen (IDEA- Participants with ≥ 50% ≥ 50% PR: PGE good or excellent at 033) gel 200 mg daily, n PR (1) 41.2% = 113/274 12 weeks: = 274 12 weeks (2) 50.5% = 142/281 (1) 54.7% = 150/274 (2) 8.8 g vehicle daily, n (2) 60.5% = 170/281 = 281 Progressive improve- ments in mean PI (37% All medication admin- red) and function (about istered in divided daily 40%) in both groups dose throughout study. Com- parable between groups

Sandelin 1997 (1) Eltenac 1% gel + No patient-reported di- No data No signiﬁcant difference placebo tablets, n = 126 chotomous outcome in VAS score between the (2) Diclofenac tablet 50 4 weeks 3 groups mg + placebo gel, n = 82 (3) Placebo gel and tablets, n = 82 Gel applied as 3 g (= 30 mg eltenac or placebo) x 3 daily, tablets x 2 daily

Simon 2009 (1) Diclofenac solution Participants with ≥ 50% 50% PR: Topical diclofenac was 1.5% (with DMSO 45. PR (from author) (1) 73/154 statistically superior to 5%, Pennsaid®) + oral 12 weeks (2) 53/155 placebo for all 3 primary placebo, n = 154 (4) 77/151 variables (pain, physical (2) DMSO (45.5%) ve- function, patient overall hicle solution + oral health assessment); supe- placebo, n = 155 riority was also observed (3) Placebo solution for PGE but not stiffness (with 2.3% DMSO) + oral placebo, n = 161 A comparison of oral (4) 100 mg slow-re- versus topical diclofenac lease oral diclofenac + found no statistically sig- placebo solution (with 2. niﬁcant difference for 3% DMSO), n = 151 any of the 5 efﬁcacy vari- Solution applied as 40 ables above drops of solution x 4 daily, tablet taken x 1 daily

Tugwell 2004 (1) Diclofenac solution OMERACT-OARSI re- ITT analyses: Mean changes in pain, (with 45.5% DMSO; sponder (1) 201/303 physical function, stiff- Pennsaid®) placebo oral 12 weeks (2) 210/301 ness, and patient assess- capsule, n = 311 ment not statistically dif- (2) Diclofenac capsule + PP analysis: ferent between groups

placebo topical solution (1) 167/236 (carrier with small quan- (2) 184/254 tity DMSO), n = 311 Solution applied as 50 drops of solution x 3 daily (daily total 4.6 mL = 75 mg diclofenac or placebo), oral capsule (50 mg diclofenac or placebo) taken x 3 daily van Haselen 2000 (1) Piroxicam 0.5% gel, PGE 6-point scale PGE excellent or good: Mean pain reduction as n = 91 4 weeks (1) 20/91 8.1/100 mm (SD 25) in (2) SRL gel: Symphy- (2) 38/89 the piroxicam group and tum ofﬁcinale (comfrey) 16.5/100 mm (SD 24.6) , Rhus toxicodendron VAS in the SRL group, (poison ivy), and Ledum an 8.4 mm difference be- palustre (marsh-tea), n = tween treatment groups 89 (95% CI 0.8 to 15.9)

Gels applied 1 g x 3 daily

Varadi 2013 (1) VALE-ibuprofen No dichotomous data No dichotomous data Mean decrease in PI on cream 4 g daily, n = 39 2 weeks walking from baseline to (2) Placebo cream, n = 36 week 2: (1) 2.0/10 (SD 2.4) All medication admin- (2) 1.6/10 (SD 1.9) istered in divided daily dose Mean improvement in function greater with ibuprofen than placebo (32% versus 16%)

Widrig 2007 (1) Ibuprofen 5% gel PGE 4-point scale PGE very good or good: Mean change in pain and (Optifen), n = 98 3 weeks (1) 56.5% = 50/85 hand function not signif- (2) Arnica 50% gel, n = (2) 64% = 57/89 icantly different between 100 groups

Gel applied as 4 cm strip x 3 daily

Zacher 2001 (1) Diclofenac Emulgel ≥ 40% PR (unclear if ≥ 40% PR - (verum) + placebo tabs, physician or patient as- modiﬁed ITT: n = 165 sessment reported) (1) 66/165 (2) Oral ibuprofen 300 3 weeks (2) 53/156 mg + placebo gel, n = 156 Gel applied x 4 daily, tabs taken x 3 daily

DMSO: dimethyl sulphoxide; ITT:intention-to-treat; n: number of participants in the treatment arm; OARSI: Osteoarthritis Research Society International; OMERACT: Outcomes Measures in Rheumatology Clinical Trials; PGE: patient global evaluation; PR: pain relief; SD: standard deviation; VAS: visual analogue scale; WOMAC: Western Ontario and McMaster Universities Arthritis Index

Appendix 7. Summary of results in individual studies - adverse events and withdrawals

Summary of outcomes: adverse events and withdrawals

Study ID Treatment Local AEs Systemic AEs Serious AEs AE withdrawals Other withdrawals

102-93-1 (1) Diclofenac (1) 21/41 No useable data None reported No data No data solution (with (2) 6/42 45.5% DMSO; Pennsaid®) (2) Con- trol (with 45.5% DMSO) (3) Placebo (with 4.55% DMSO) Solution applied as 40 drops (about 1 mL) x 4 daily Number of participants in each group not reported

108-97 (1) Diclofenac Com- No data None reported (1) 7/48 No data solution (with mon, almost ex- (2) 3/47 45.5% DMSO; clusively of dry- Pennsaid®), n = ness and other 48 minor events at (2) Con- the site of appli- trol (with 45.5% cation - of mini- DMSO), n = 47 mal practical sig- (3) Diclofenac nif- solution (with 2. icance for com- 3% DMSO), n = pliance or safety 50 (4) Placebo (with 2.3% DMSO), n = 50 Solution applied

4 x daily to maximum 40 drops per hand

Altman 2009 (1) Diclofenac “Application-site Any AE (sys- None reported (1) 10/198 LoE: sodium gel 1% reactions” temic or local) (2) 4/187 (1) 8/198 (Voltaren) with (1) 4.5% = 9/ (1) 52% = 103/ (2) 13/187 vehicle 2 g, n = 198 198 Lost to follow- 198 (2) 2.1% = 4/ (2) 43.9% = 82/ up: (2) Placebo gel 187 187 (1) 2/198 (vehicle carrier) Most common: Most common: (2) 1/187 n = 187 paraesthesia headache Withdrew con- Gels applied x 4 GI AE: sent, protocol daily (1) 7.6% = 15/ deviation, admin 198 problem: (2) 3.7% = 7/ (1) 5/198 187 (2) 8/187 Only 2 in (1) judged related to treatment Most mild. Most common: diarrhoea, no ulcers or GI bleeds

Baer 2005 (1) Di- (1) 42/107 GI events more None reported (1) 9/107 LoE: clofenac sodium (2) 23/109 frequent with (1) (2) 9/109 (1) 8/107 1.5% (with 45. Most common: . Most common, (2) 4/107 5% DMSO; dry skin abdominal pain (Skin-related): Other: Pennsaid®), n = and dyspepsia (1) 5/107 (1) 18/109 107 (2) 0/109 (2) 12/109 (2) Placebo (ve- 2 in each group hicle carrier), n = excluded due to 109 major violations Solution applied of entry criteria as 40 drops x 4 daily

Balthazar- (1) Diclofenac None observed None observed None None Lost to follow- Letawe 1987 (Voltaren Emul- up: gel), n = 25 (1) 8/25 (2) In- (2) 6/25 domethacin (In- docid) gel, n = 25 Gels applied x 2 daily

Baraf 2011 (1) Di- Dermatitis Any AE (sys- (1) 12/721 (1) 39/721 LoE: clofenac sodium (1) 34/721 temic or local): (2) 5/705 (2) 18/705 (1) 32/721

gel 1%, n = 721 (2) 4/705 (1) 406/721 One in (1) con- (2) 51/705 (2) Placebo gel (2) 340/705 sidered related to Lost to follow- (vehicle only), n GI AEs infre- treatment (DVT up: = 705 quent and PE (1) 14/721 Medication ap- in woman with (2) 26/705 plied 4 x 4 g daily Most com- multiple risk fac- Withdrew con- mon: headache, tors) sent, protocol arthralgia, back 1 death in (1) deviation, admin pain judged unrelated problem: to treatment (AF (1) 46/721 with mul- (2) 58/705 tiple pre-existing medical problems)

Bolten 1991 (1) Felbinac gel (1) 2/142 (1) 1/142 (gen- None reported None No data 3% 1 g, n = 142 (2) 4/139 eralised itching) (2) Placebo gel, n All skin AEs No other AEs = 139 resolved without mentioned Gel applied x 3 treatment daily

Bookman 2004 (1) Diclofenac (1) 30/84 GI AEs did not None reported (1) 5/84 LoE: solution 1.5% in (2) 11/80 differ (2) 3/80 (1) 2/84 DMSO (45.5%: (3) 1/84 between groups. (3) 0/84 (2) 8/80 Pennsaid®), n = Most common: Most common: (3) 10/84 84 dry skin dyspepsia Other medical/ (2) Carrier with Re- personal reason: DMSO (45.5%) versible on stop- (1) 3/84 , n = 80 ping treatment (2) 3/80 (3) Carrier with (3) 5/84 1/10th DMSO (4.55%), n = 84 Solution applied as 40 drops (= 1. 3 mL) x 4 daily

Bruhlmann (1) Di- (1) 3/51 (2 rash, (1) 1/51 (nausea) None (1) 1/51 LoE: 2003 clofenac sodium 1 pruritus) (2) 1/52 (weak- (2) 2/52 (1) 1/51 patch 1% (180 (2) 2/52 (1 rash, ness/dizziness) (2) 3/52 mg; Flector-EP), 1 local heat) Other (lost to n = 51 follow-up, pro- (2) Placebo tocol violation): patch, n = 52 (1) 0/51 Patch applied x 2 (2) 3/52 daily

Burgos 2001 (1) Flurbiprofen (1) 2/61 (1 rash, (1) 4/64 None reported (1) 1/64 LoE: LAT (= 40 mg) + 1 contact der- (2) 4/65 (2) 1/65 (1) 2/64 placebo cream, n matitis) (2) 3/65 = 64 (2) 1/60 (1 rash/ Other: (2) Piketoprofen pruritus) (1) 3/64 cream 1.8% (4 (2) 5/65 cm ~ 36 mg) + Mild placebo patch, n intensity, disap- = 65 peared on dis- Patch applied x 2 continuing treat- daily, cream x 3 ment daily

Conaghan 2013 (1) Ke- (1) 13/233 GI disorders: (1) 0/233 (1) 3/233 LoE: toprofen (IDEA- (2) 28/230 (1) 3/233 (2) 3/230 (2) 13/230 (1) 7/233 033) gel 100 mg (3) 14/238 (2) 3/230 (3) 3/238 (3) 6/238 (2) 4/230 daily, n = 233 (4) 26/234 (3) 2/238 (4) 4/234 (4) 9/234 (3) 5/238 (2) Ketoprofen (5) 5/233 (4) 7/234 (5) 4/233 (5) 13/233 (4) 8/234 (IDEA-033) gel (6) 2/227 (5) 37/233 (6) 1/227 (6) 13/227 (5) 5/233 200 mg daily, n = (6) 33/227 (6) 21/227 230 No SAEs consid- (3) 4.4 g vehicle No numbers for ered treatment- Other: daily, n = 238 patients with any related (1) 3/233 (4) 8.8 g vehicle systemic AE, but (2) 13/230 daily, n = 235 numbers for AEs No deaths (3) 6/238 (5) Oral cele- other than GI are (4) 7/234 coxib 200 mg low (5) 13/233 daily. N = 235 (6) 13/227 (6) Oral placebo, n = 228 All medication administered in divided daily dose (vehicle = TDT- 064)

Dickson 1991 (1) Piroxicam gel (1) (1) 30/117 (12 None (1) 9/117 (1) 7/117 0.5% (1 g = 5 3/117 (1 rash, 1 upper (2) 7/118 (2) 16/118 mg piroxicam) + bruising, 1 ery- GI, 3 other GI, 7 placebo tablet, n thema of knee CNS, 8 other) = 117 (rubbing)) (2) 27/118 (10 (2) Ibuprofen (2) 4/118 upper tablet 400 mg + (1 rash, 2 depen- GI, 1 other GI, 8 placebo cream, n dant oedema, CNS, 8 other) = 118 1 local heat/ery- mg x 3 daily, n = thema (rubbing) 118 ) Gels applied x

3 daily, tablet taken x 3 daily

Dreiser 1993 (1) Diclofenac (1) 1/78 (1) 0/78 None (1) 0/78 LoE: (DHEP) patch (2) 2/77 (2) 2/77 (nau- (2) 1/ (1) 0/78 (= 180 mg), n = (in- sea and vomit- 77 (oedema be- (2) 9/77 78 termittent itch, ing, oedema un- neath plaster) Other: (2) Placebo resolved sponta- der plaster) (1) 1/78 patch, n = 77 neously) (2) 3/77 Patch applied x 2 daily

Ergun 2007 (1) Nimesulide (1) 2/51 None reported None None 2 gel 1% (Sulidin) (2) 1/23 from each group 0.4 mg/10 cm2, (itching - mild) lost to follow-up n = 51 (2) Placebo gel, n = 23 Gels applied x 3 daily

Galeazzi 1993 (1) Diclofenac None None None None None (DHEP) plaster (= 180 mg diclofenac derivative), n = 30 (2) Placebo plaster, n = 30 Plasters applied x 2 daily

Grace 1999 (1) (1) 4/38 (rash) (1) 2/38 (1 nau- None (1) 1/38 (rash) (1) 0/38 Diclofenac (with (2) 7/36 (5 rash, sea, 1 hirsutism) (2) 0/36 (2) 3/36 (lost to lecithin) gel 2% 1 numbness, 1 (2) 2/36 (2 nau- follow-up/pro- (2.5 g), n = 38 pruritis) sea) tocol violation) (2) Placebo gel, n All mild = 36 Gels applied as 1 scoop 3 x daily

Gui 1982 (1) Ibupro- None None None None No data fen cream, n = 20 (strength, dose, quantity not reported) (2) Placebo cream, n = 20 Creams applied x 2 daily

Hohmeister (1) Flufenamate (1) 8/49 No data None reported None None 1983 3% plus salicy- (2) 0/51 late 2% gel (Mo- bilisin), n = 49 (quantity not reported) (2) Placebo gel, n = 51 Gels applied x 3 daily

Kneer 2013 (1) Ke- (1) 31223 GI disorders: None reported (1) 9/223 LoE: toprofen (IDEA- (2) 43/223 (1) 6223 (2) 15/223 (1) 15/223 033) gel 50 mg (3) 53/221 (2) 6/223 (3) 16/221 (2) 14/223 daily, n = 223 (4) 39/199 (3) 10/221 (4) 8/199 (3) 6/221 (2) Ketoprofen (4) 9/199 (4) 12/199 (IDEA-033) gel Most of mild or 100 mg daily, n = moderate inten- No numbers for Other: 223 sity and resolved participants with (1) 15/223 (3) Ketoprofen without action any systemic AE. (2) 9/223 (IDEA-033) gel Num- (3) 13/221 200 mg daily, n = No photoallergic bers with mus- (4) 16/199 221 contact dermati- culoskeletal and (4) Vehicle, n = tis connective tissue 199 dis- All med- orders, and ner- ication adminis- vous system dis- tered in divided orders > 10% daily dose

Link 1996 (1) Ketoprofen No data No data No data No data All withdrawals gel 2.5%, n = 56 (1) 5/56 (2) Placebo gel, n (2) 8/59 = 59 Gels applied as 4 to 10 cm strip x 3 or 4 daily

McCleane 2000 (1) Piroxicam gel None reported (1) 1/50 (nausea) None reported (1) 1/50 Other: 2.5%, n = 40 (2) 0/50 +* (4) 0/50 (1) 10/50 (2) GTN 1%, n (3) 1/50 (dys- (4) 4/50 = 36 pepsia) (3) Piroxicam gel (4) 1/50 (nausea) 2.5%/GTN 1%, +* n = 37 (4) Placebo gel, n *17/100 partici- = 46 pants who had Gels applied as GTN developed “small volume” x

3 daily headaches associated with the cream

NCT01980940 (1) Not separately Any AE (sys- None None None Etoricoxib gel 50 reported temic or local): mg, 4% DMSO, (1) 6/24 n = 24 (2) 5/24 (2) Placebo gel, n = 24

Niethard 2005 (1) Diclofenac 1. (1) 4/117 Any AE (sys- (1) 0/117 (1) 2/117 LoE: 16% gel (2) 3/120 temic or local): (2) 1/120 (brain (2) 0/120 (1) 1/117 (Voltaren (1) 11/117 tumour) (2) 2/120 Emugel), n = Reversible when (2) 11/120 Other: 117 treatment (1) 2/117 (2) Placebo gel, n stopped (2) 5/120 = 121 Excluded due to Gels applied 4 g protocol x 4 daily violations: (1) 10/117 (2) 16/120

Ottillinger 2001 (1) Eltenac gel No useable data 17 AEs in 16/ None reported (1) 0/57 LoE: 1% 3 g, n = 57 237 participants (2) 0/59 (1) 0/57 (2) Eltenac gel 0. (did not report (3) 0/59 (2) 0/59 3% 3 g, n = 59 which group/na- (4) 1/59 (3) 1/59 (3) Eltenac gel 0. ture of reaction) (4) 0/59 1% 3 g, n = 59 Other “non (4) Placebo gel, n medical” reason: = 59 (1) 0/57 Gels applied as 4 (2) 0/59 inch string (ap- (3) 4/59 prox 3 g) x 3 (4) 1/59 daily; to give 9 mg, 27 mg, 90 mg daily doses, or placebo

Poul 1993 (1) Flurbiprofen (1) 3/53 (1 skin Any AE: None reported (1) 2/53 (1 LoE: LAT patch, 40 bruising, 2 mild (1) 8/53 skin irritation, 1 (1) 2/53 mg, n = 53 skin redness) (2) 3/51 UTI) (2) 1/51 (2) Placebo (2) 0/51 (2) 2/51 (sore- Other: patch, n = 51 ness at treatment (1) 10/53 Medication ap- site and nausea (2) 8/51 plied as patch x 2 from odour of daily patch)

Rose 1991 Piroxicam (1) 1/15 None reported None reported No data No data gel 5% (5 mg), n (2) 1/15 = 15 Placebo gel, n = 15 Gels applied 1 mg x 4 daily

Roth 1995 Diclofenac 3% + (1) 12/59 (7 pru- No data None reported Not reported All withdrawals: hyaluron 2.5% ritis, 5 rash) (1) 3/59 gel, n = 59 (2) 26/60 (15 (2) 4/60 Placebo pruritis, 11 rash) + hyaluron 2.5% gel, n = 60 Gels applied 2 g x 4 daily

Roth 2004 (1) Diclofenac 1. Most common - GI AE: None reported (1) 8/164 LoE: 5% with DMSO dry skin: (1) 19/164 (2) 4/162 (1) 28/164 (45.5%; (1) 60/164 (2) 15/162 (2) 42/162 Pennsaid®), n = (2) 41/162 Other: Lost to follow- 164 Rash: (1) 21/164 up: (2) Carrier with (1) 18/164 (2) 17/162 (1) 3/164 DMSO (45.5%) (2) 8/162 (2) 0/162 , n = 162 Reversible on Other: Solution applied withdrawal (1) 6/164 as 40 drops x 4 (2) 7/162 daily

Rother 2007 (1) Ketopro- Any skin/subcu- GI AE: (1) 0/138 (1) 23/138 LoE: fen gel (IDEA- taneous tissue: (1) 13/138 (2) 1/132 (MI) (2) 18/132 (1) 1/138 33) 110 mg + (1) 39/138 (2) 18/132 (3) 1/127 (3) 20/127 (2) 3/132 placebo tabs, n = (2) 27/132 (3) 12/127 (angina) (3) 3/127 138 (3) 28/127 Lost to follow- (2) Celecoxib Generally mild, No GI bleeding up: tabs 100 mg + reversible (1) 1/138 placebo gel, n = Other: 132 (1) 0/138 (3) Placebo gel (2) 2/132 and tabs, n = 127 (3) 2/127 Gel applied x 2 daily, tablet taken x 2 daily

Rother 2013 (1) Ke- (1) 29/274 GI disorders: (1) 3/274 (1) 20/274 LoE: toprofen (IDEA- (2) 32/281 (1) 2/274 (2) 4/281 (2) 12/281 (11/ (1) 16/274 033) gel 200 mg (2) 2.281 281 in ﬂow (2) 18/281 daily, n = 274 More than 50% 1 event in (1) chart) (2) 8.8 g vehicle

daily, n = 281 were mild No “treatment- possibly related Other: related” cardiac to study medica- (1) 28/274 All med- or vascular AE tion - headache (2) 29/281 ication adminis- reported tered in divided daily dose

Sandelin 1997 (1) Eltenac (1) 16/126 (ery- (1) 25/126 (6 None reported (1) 4/126 (local 3 for non med- 1% gel + placebo thema, eczema, GI, 12 CNS, 7 reaction) ical reasons, 6 tablets, n = 126 itching,rash, dry other) (2) 1/82 had disease other (2) skin) (2) 21/82 (11 (abdominal pain than OA Diclofenac tablet (2) 1/82 GI, 6 CNS, 4 + diarrhoea) 50 mg + placebo (3) 5/82 other) (3) 1/82 (local gel, n = 82 (3) 13/82 (6 GI, reaction) (3) Placebo gel 4 CNS, 13 and tablets, n = other) 82 Gel applied as 3 g (= 30 mg eltenac or placebo) x 3 daily, tablets x 2 daily

Simon 2009 (1) (1) 41/154 GI AE (most (1) 0/154 (1) 16/154 LoE: Diclofenac solu- (2) 12/157 common): (2) 4/157 (2) 18/157 (1) 16/154 tion 1.5% (with (3) 27/161 (1) 10/154 (3) 1/161 (3) 12/161 (2) 18/155 DMSO 45. (4) 11/151 (2) 15/157 (4) 1/151 (4) 19/151 (3) 17/161 5%, Pennsaid®) (5) 47/152 (3) 18/161 (5) 3/152 (5) 23/152 (4) 5/151 + oral placebo, n (4) 36/151 (5) 9/151 = 154 Most common: (5) 39/152 (2) DMSO (45. dry skin at the Consent 5%) vehicle solu- application site, Other system withdrawn: tion + oral contact dermati- events: (1) 6/154 placebo, n = 155 tis at the appli- (1) 27/154 (2) 6/155 (3) Placebo solu- cation site, and (2) 18/157 (3) 10/161 tion (with 2.3% rash (3) 21/161 (4) 8/151 DMSO) + oral (4) 26/151 (5) 8/151 placebo, n = 161 (5) 21/152 (4) 100 mg slow- Lost to follow- release Includ- up: oral diclofenac + ing such things (1) 2/154 placebo as headache, (2) 4/155 solution (with 2. back pain, and (3) 3/161 3% DMSO), n = arthralgia (4) 2/151 151 (5) 2/151 Solution applied as 40 drops of so- “Other”: lution x 4 daily, tablet taken x 1

daily (1) 11/154 (2) 8/155 (3) 6/161 (4) 10/151 (5) 9/151

Tugwell 2004 (1) Diclofenac Most common - GI AE: None reported (1) 64/311 LoE: solution (with dry skin: (1) 108/311 (2) 79/311 (1) 28/311 45.5% DMSO; (1) 83/311 (2) 150/311 (2) 10/311 Pennsaid®) (2) 4/322 More partic- Lost to follow- placebo oral cap- ipants had severe up: sule, n = 311 Rash: GI AEs with oral (1) 5/311 (2) Di- (1) 36/311 than topical (2) 5/311 clofenac capsule (2) 5/322 “Other”: + placebo topical More partici- (1) 32/311 solution (carrier Mostly mild and pants had lab ab- (2) 22/311 with small quan- reversible normalities with tity DMSO), n = oral than topical 311 Solution applied as 50 drops of solution x 3 daily (daily total 4.6 mL = 75 mg diclofenac or placebo) , oral capsule (50 mg diclofenac or placebo) taken x 3 daily van Haselen (1) Piroxicam 0. (1) 7/89 (1) 5/89 Not reported (1) 1/89 Did not start 2000 5% gel, n = 91 (2) 11/91 (2) 5/91 (2) 1/91 treatment/lost to (2) SRL gel: Sym- follow-up: phytum ofﬁcinale (1) 5/89 (comfrey), Rhus (2) 2/91 toxicodendron (poison ivy), and Ledum palustre (marsh- tea), n = 89

Gels applied 1 g x 3 daily

Varadi 2013 (1) VALE- (1) 1/30 None None Not reported (1) 3 participants ibuprofen cream (2) 1/31 terminated early, 4 g daily, n = 39 Note - not ITT 2 excluded from (2) Placebo Mild rash analysis for pro-

cream, n = 36 tocol violations (2) 1 participant All med- terminated early, ication adminis- 4 excluded from tered in divided analysis for pro- daily dose tocol violations

Widrig 2007 (1) Ibuprofen No useable data Any AE: (1) 0/98 (1) 1/98 Exclu- 5% gel (Optifen) Mostly skin reac- (1) 8/98 (2) 1/100 (back (2) 3/100 (back sions due to pro- , n = 98 tions (2) 14/100 trauma due to pain) tocol violations: (2) Arnica 50% fall) 1 in (1) and 2 in (1) 12/98 gel, n = 100 (2) had “early in- (2) 9/100 tolerance of gel” Gel applied as 4 cm strip x 3 daily

Zacher 2001 (1) Diclofenac No useable data Any AE: (1) 0/165 (1) 5/167 No data or miss- Emulgel (verum) (1) 36/165 (2) 1/156 (ileus, (2) 16/160 ing data + placebo tabs, n (2) 42/156 judged unrelated (1) 6/165 = 165 GI AE: to medication) (2) 4/156 (2) Oral ibupro- (1) 15/165 (added back in to fen 300 mg + (2) 22/156 analyses) placebo gel, n = Excluded 156 from PP analysis Gel applied x 4 due to protocol daily, tabs taken violations: x 3 daily (1) 9/165 (2) 6/156

AE: adverse event; AF: atrial ﬁbrillation; CNS: central nervous system; DMSO: dimethyl sulfoxide; DVT: deep vein thrombosis; GI: gastrointestinal; GTN: glycerine trinitrate; LoE: lack of efﬁcacy; n: number of participants in the treatment arm; OA: osteoarthritis; PE: pulmonary embolism; PP: per protocol

WHAT’S NEW Last assessed as up-to-date: 3 February 2016.

Date Event Description

11 February 2016 New citation required and conclusions have changed Five new included studies, principally with topical ketoprofen (almost 3000 additional participants, a 38% increase) Two studies awaiting classiﬁcation (additional details sought). Three ongoing studies identiﬁed in clinical trial registries. Twelve studies that are completed, but for

which no results are available, identiﬁed in clinical trial registries Conclusions not changed for diclofenac. New data for topical ketoprofen in this update. New interpretation of possible beneﬁcial effects of carrier, as well as NSAID

3 February 2015 New search has been performed New searches run and new studies identiﬁed.

HISTORY Protocol ﬁrst published: Issue 4, 2008 Review ﬁrst published: Issue 9, 2012

Date Event Description

30 June 2009 Amended Spelling of title corrected.

12 November 2008 Amended Contact details updated.

CONTRIBUTIONSOFAUTHORS For the original review Roy Rabbie and SD identiﬁed studies, and carried out data extraction, analysis and drafting. RAM was involved in planning, acted as adjudicator, and was involved with writing. For this update SD and RAM identiﬁed studies, and carried out data extraction, ’Risk of bias’ assessment, and analysis. PC and JdaS provided much insight into the clinical contexts of the use of topical NSAIDs. All authors contributed to writing the full review. SD will be responsible for updating the review.

DECLARATIONSOFINTEREST SD: none known. PC is a specialist rheumatologist and manages patients with chronic musculoskeletal pain. He was an author of two studies included in this review. He was not involved in data coding or data extraction for these studies. He has received speaking fees from Abbvie, BMS, and Roche (2013). JdS is a specialist rheumatologist and manages patients with chronic musculoskeletal pain. PW: none known. RAM: has received institutional grant support from Reckitt Benckiser (RB) relating to individual patient level analyses of trial data on ibuprofen in acute pain and the effects of food on drug absorption of analgesics (2013), and from Grünenthal relating to individual patient level analyses of trial data regarding tapentadol in osteoarthritis and back pain (2015). He has received honoraria for attended boards with Menarini concerning methods of analgesic trial design (2014), with Novartis (2014) about the design of network meta-

Topical NSAIDs for chronic musculoskeletal pain in adults (Review) 112 Copyright © 2016 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. analyses, and RB on understanding pharmacokinetics of drug uptake (2015). None of these activities was related to topical NSAIDs. Novartis and/or its subsidiaries may market a diclofenac gel product; Menarini or its subsidiaries markets a ketoprofen gel product; and RB or its subsidiaries markets an ibuprofen gel product. As far as is known, only diclofenac gel product is licensed for use in osteoarthritis.

SOURCES OF SUPPORT

Internal sources • Oxford Pain Relief Trust, UK. General institutional support

External sources • The National Institute for Health Research (NIHR), UK. NIHR Cochrane Programme Grant: 13/89/29 - Addressing the unmet need of chronic pain: providing the evidence for treatments of pain

DIFFERENCESBETWEENPROTOCOLANDREVIEW Since the protocol for this review was published the ’Risk of bias’ tool has been introduced to RevMan. We have used this tool and removed the Oxford Validity Score because it assesses similar criteria. We have also used the GRADE system to assign grade of evidence (GRADEpro GDT 2015) and included a ’Summary of ﬁndings’ table. The original protocol planned to use four weeks as the cut-off point for analysis by study duration. Recent advances in our understanding of potential biases in studies suggest slightly different cut-off points (PaPaS 2012). For this update we have analysed data according to study duration of ≥ 2 to < 6 weeks, and of 6 to 12 weeks.

INDEX TERMS

Medical Subject Headings (MeSH) Administration, Topical; Anti-Inﬂammatory Agents, Non-Steroidal [∗administration & dosage; adverse effects]; Chronic Pain [∗drug therapy]; Diclofenac [administration & dosage; adverse effects]; Musculoskeletal Pain [∗drug therapy]; Randomized Controlled Trials as Topic

MeSH check words Adult; Humans